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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

Background

: The management of dyspepsia is controversial.

Methods

: An international Working Party was convened in 1998 to review management strategies for dyspepsia and functional dyspepsia, based on a review of the literature and best clinical practice.

Results

: Dyspepsia, defined as pain or discomfort centred in the upper abdomen, can be managed with reassurance and over-the-counter therapy if its duration is less than 4 weeks on initial presentation. For patients with chronic symptoms, clinical evaluation depends on alarm features including patient age. The age cut off selected should depend on the age specific incidence when gastric cancer begins to increase, but in Western nations 50 years is generally an acceptable age threshold. In younger patients without alarm features, Helicobacter pylori test and treatment is the approach recommended because of its value in eliminating the peptic ulcer disease diathesis. If, after eradication of H. pylori, symptoms either are not relieved or rapidly recur, then an empirical trial of therapy is recommended. Similarly, in H. pylori-negative patients without alarm features, an empirical trial (with antisecretory or prokinetic therapy depending on the predominant symptom) for up to 8 weeks is recommended. If drugs fail, endoscopy should be considered because of its reassurance value although the yield will be low. In older patients or those with alarm features, prompt endoscopy is recommended. If endoscopy is non-diagnostic, gastric biopsies are recommended to document H. pylori status unless already known. While treatment of H. pylori is unlikely to relieve the symptoms of functional dyspepsia, the long-term benefits probably outweigh the risks and treatment can be considered on a case-by-case basis. In H. pylori-negative patients with documented functional dyspepsia, antisecretory or prokinetic therapy, depending on the predominant symptom, is reasonable, assuming reassurance and explanation are insufficient, unless patients have already failed this approach. Other treatment options include antidepressants, antispasmodics, visceral analgesics such as serotonin type 3 receptor antagonists, and behavioural or psychotherapy although these are all of uncertain efficacy. Long-term drug treatment in functional dyspepsia should be avoided; intermittent short courses of treatment as needed is preferred.

Conclusion

: The management of dyspepsia recommended is based on current best evidence but must be tailored to local factors such as practice setting, the background prevalence of H. pylori and structural disease, and costs.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

While there have been many definitions proposed for dyspepsia, the most widely accepted and authoritative remains the Rome criteria, which defines dyspepsia as chronic or recurrent pain or discomfort centred in the upper abdomen.1 The criteria imply that pain or discomfort in the central upper abdomen must be the predominant complaint if the patient is to be labelled as having dyspepsia. This helps to differentiate dyspepsia from gastro-oesophageal reflux disease (GERD), where the predominant complaint is typically heartburn or acid regurgitation, although epigastric pain may often be present.2[3]–4

Dyspepsia is a remarkably common symptom complex. The point prevalence varies from 25% to 40% although the higher rates appear to be explained by the inclusion of subjects with typical GERD.5 In a population-based endoscopic study from northern Norway, among those with epigastric pain only 9% had a peptic ulcer and 14% oesophagitis.6 Numerous other studies have demonstrated that peptic ulcer disease, reflux oesophagitis and cancer account for only a minority of dyspepsia cases; the remainder have minor abnormalities of uncertain significance or an entirely normal endoscopy, and are labelled as having functional (or non-ulcer) dyspepsia.7, 8 The value of additional diagnostic testing in patients with this label is probably very limited. The yield from abdominal ultrasound is very low.9[10]–11 Although Klauser et al. reported finding a possible explanation for symptoms in 47% after an extensive battery of tests,11 the clinical significance of many of these diagnoses is highly questionable with the exception of GERD based on 24-h oesophageal pH testing. In contrast, Nyren et al. did not find additional diagnostic testing of value in endoscopy negative dyspepsia.9

In agreement with the Rome definition, this Working Party concludes that the term functional dyspepsia should refer to patients who have as their predominant complaint persistent or recurrent pain or discomfort centred in the upper abdomen, where there is no definite structural or biochemical explanation for the symptoms after clinically appropriate investigations have been undertaken. Functional dyspepsia includes patients with Helicobacter pylori gastritis, gastroduodenal motility disturbances, visceral hypersensitivity and other pathophysiological disturbances which are currently of uncertain or doubtful clinical significance.12, 13 While the disorder has a benign course, it is usually a life-long problem.14, 15

When considering the management of the new patient with dyspepsia or the patient presenting for the first time with dyspepsia, a number of issues need to be considered. The clinician is interested in what potentially may be causing the symptoms and in particular whether serious structural disease is present. On the other hand, what is bothering the patient may not necessarily be the presenting gastrointestinal symptoms;16 psychosocial factors including fear of serious disease may be important in driving patients with dyspepsia to seek health care.17[18]–19 The clinician needs to determine whether investigations are necessary either for reassurance or to identify serious disease, and if so which ones. Next, a decision about the appropriateness of drug therapy, which drug and for how long needs consideration. The latter depends on the provisional diagnosis which may need to be refined later if the patient does not respond appropriately to initial therapy.

In 1985, the American College of Physicians published guidelines for the management of dyspepsia based on a review of the literature.20 It was suggested that a trial of therapy was appropriate initially in most patients. The guidelines emphasized the need to clinically search for alarm features which would point to a more serious diagnosis. In the absence of alarm features, a trial of antisecretory treatment was recommended for 4–8 weeks. If there was little or no response within seven to 10 days, or symptoms failed to resolve by 8 weeks than an upper endoscopy was recommended. However, the discovery of H. pylori and recognition of its link to peptic ulcer disease and its possible relationship with functional dyspepsia has impacted on approaches to management. This change reflects the recognition that peptic ulcer disease is usually a curable infectious disease due to H. pylori infection, and it is no longer appropriate or desirable to treat peptic ulcer disease with traditional antisecretory therapy alone.21[22][23]–24

There are at least four major strategies for the management of dyspepsia that require careful consideration. Firstly, there is a wait-and-see strategy of reassurance or over-the-counter antacids or H2-receptor blockers, with re-evaluation if this fails. Secondly, there is an empirical therapy strategy (e.g. prescribing an antisecretory or prokinetic agent), reserving endoscopy or other testing for those who are unresponsive or have an early symptomatic relapse. Thirdly, there is a stratified approach. Here management is based on symptom patterns or H. pylori status, with the goal of targeting further treatment and investigations more appropriately. The final approach is to refer all patients with dyspepsia for prompt upper endoscopy. Each of these strategies has strengths and weaknesses (Table 1).

Table 1.  . Strategies for the management of uninvestigated dyspepsia Thumbnail image of

This Working Party was convened for the World Congresses of Gastroenterology in 1998. The mandate was to gather investigators from different parts of the world with a major interest in dyspepsia to provide an expert report on the management of dyspepsia and functional dyspepsia. The report was sponsored by the Scientific Co-ordinating Committee. Pharmaceutical companies were not invited to provide input into the meeting or report. The Working Party reviewed the available literature on management of dyspepsia in order to generate this report. Initially, an extensive Medline search from 1985 to September 1998 was conducted using the MeSH term dyspepsia, and literature cited in previous consensus meeting reports was reviewed.13, 21[22][23]–24 This was followed by a round table meeting to review the available data and design the most optimal strategy based on the best available evidence. In this report, the background literature will be first reviewed and then the management algorithm described, with supporting evidence provided where available. Where evidence was not available, the Working Party applied clinical judgement and this is explicitly described in the management plan that follows.

SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

Because there are multiple symptoms in patients with dyspepsia, in 1988 it was proposed that dyspepsia could be subdivided into dyspepsia subgroups.25 The proposal was further refined by the Rome Working Party, and specific groups of symptoms were identified by consensus for ulcer-like and dysmotility-like dyspepsia; reflux-like dyspepsia was considered synonymous with symptomatic GERD.1 It was anticipated that these groups of symptoms would be helpful in identifying more homogeneous populations who would respond to targeted pharmacological therapy. Unfortunately, the approach has failed to live up to expectations. The use of symptom subgroups has been disappointing in large part because of the extensive overlap of the subgroups based on symptom groupings and because a substantial proportion could not be classified using this approach at all (unspecified dyspepsia).26 More importantly, the symptom subgroups have not been particularly useful in identifying relevant underlying disease. For example, the prevalence of peptic ulcer disease in ulcer-like dyspepsia was 9% compared with 7% in dysmotility-like dyspepsia.27 The reflux-like dyspepsia group has unfortunately caused the most confusion as a distinction from symptomatic GERD was not made clear initially. If reflux-like dyspepsia is defined as the presence of upper abdominal pain plus frequent reflux symptoms, approximately one in 10 of these patients will also have peptic ulcer disease.27 While oesophagitis is more common in the reflux-like dyspepsia group, unfortunately there is a substantial group with ulcer-like and dysmotility-like dyspepsia who also have oesophagitis.27 Symptom scoring systems28, 29 have similarly been disappointing when subjected to prospective validation.30, 31 Based on the available studies, symptom patterns do not help the clinician decide whether dyspepsia is the result of structural or functional disease.32[33]–34

ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

Age has been applied as a means of identifying those at higher risk of having structural disease. Traditionally, an age of over 45 years has been used since the American College of Physicians guidelines. Indeed, the presence of gastric cancer is very rare below age 45 years, while its incidence rapidly increases thereafter in Western nations.35, 36 Furthermore, initial data suggest that being older than 40 years is an independent risk indicator for identifying structural disease at endoscopy,37, 38 although not all studies agree.39 Recently, data from the UK suggest that an age threshold of above 55 years may now be more appropriate.36 This differs from some countries in the Asian Pacific region, where the age specific incidence of gastric cancer begins to rise after the age of 35 years and therefore a lower age threshold appears more appropriate.23

The Working Party concludes that the age threshold is useful, but that the cut off must be defined for each region based on the known age specific incidence of gastric cancer. In most Western countries, an age threshold of 50 years is probably appropriate, as it is for colon cancer screening, although it is recognized that a very small number of patients with gastric cancer will be missed if this age threshold is applied.

The value of alarm symptoms and signs for identifying those at a higher risk of structural disease is based largely on clinical judgement as there are few available studies in the literature. The alarm features that are traditionally applied include weight loss, vomiting, progressive dysphagia, odynophagia, bleeding, anaemia, jaundice, an abdominal mass, lymphadenopathy, a family history of upper gastrointestinal cancer or previous gastric surgery. The predictive value of these clinical features for detecting structural disease, however, is relatively poor. In one study, organic disease was found in only 42% with a history of bleeding and 32% with dysphagia.39 Weight loss exceeding 3 kg was higher among patients with gastric cancer (85%) than gastric ulcer (61%), duodenal ulcer (44%) and functional dyspepsia (32%),40 and weight loss was also associated with the presence of a malignancy in a prospective Scottish study.29 The absence of alarm symptoms in young dyspeptic patients presenting for endoscopy, however, appears to be a reliable indicator that gastrointestinal malignancy is not present.41

The Working Party concludes that at this time it is reasonable to advise prompt endoscopy for patients with alarm features based on good clinical practice, although the exact predictive value of each of these features remains relatively poorly documented in the literature.

PROMPT ENDOSCOPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

There is evidence that patients who receive prompt endoscopy do have a better outcome than those who are prescribed empirical H2-blocker therapy. Bytzer et al. in a randomized trial found that prompt endoscopy was followed by significantly greater symptom improvement and satisfaction scores at 4 weeks compared with those randomized to empirical H2-blocker therapy.42 Furthermore, two thirds of patients in the empirical therapy group were eventually endoscoped during the 12 months follow up. Others have shown that patients with dyspepsia after endoscopy appear to be reassured18, 43 and require fewer prescriptions.44

Endoscopy, on the other hand, is invasive and expensive, which is the main reason why this cannot be applied to all patients with dyspepsia. Unsedated transnasal or peroral out-patient upper endoscopy with small caliber endoscopes may be cheaper and appears to be well tolerated,45 and hence may make endoscopy a more cost-effective option. However, it is likely that endoscopy services would be overwhelmed if all patients with dyspepsia who present for investigation are recommended for an endoscopic procedure. While the risks of endoscopic complications are extremely low with diagnostic upper endoscopy, these are not zero and in view of the very high prevalence of dyspepsia this also weighs against recommending prompt endoscopy for all consulters.46

EMPIRIC THERAPY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

While empirical therapy has been a traditional approach for the management of patients with dyspepsia who do not have alarm features, the value of this approach has been questioned despite the safety of the drugs used. In particular, there have been concerns that patients with peptic ulcer will be inadequately or inappropriately treated with empirical antisecretory or prokinetic therapy. Indeed, empirical antisecretory therapy may heal peptic ulcer disease and result in a misdiagnosis in those undergoing endoscopy. Moreover, it seems likely that therapy often only postpones eventual investigation and thus this approach is not likely to be truly cost effective.47

TESTING FOR H. PYLORI

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

The rationale for testing for H. pylori in patients with dyspepsia is to help identify patients with peptic ulcer disease or gastric cancer who require appropriate management. McColl et al. in Scotland have shown that among patients presenting to their doctor with dyspepsia who had a positive urea breath test (a ‘gold standard’ technique for the diagnosis of H. pylori), 40% had duodenal ulcer, 13% gastric ulcer, 1% a deformed duodenum and 2% erosive duodenitis, while 12% had oesophagitis.48 This was in striking contrast to those who were urea breath test negative where only 2% had duodenal ulcer and 3% gastric ulcer, while 17% had oesophagitis. Other studies from Europe and New Zealand suggest that between 20% and 60% of patients with dyspepsia who have evidence of H. pylori infection based on a positive non-invasive test have underlying peptic ulcer disease,49[50]–51 although a low predictive value has been observed in Australia.52

H. pylori testing identifies those at high risk of peptic ulcer in contrast to the limitations of symptom scores. However, in practice, many serological tests, unlike urea breath tests, have a sensitivity and specificity of approximately 80% or lower, rather than over 90%.53 Moreover, the value of a non-invasive test depends on the positive and negative predictive value, which in turn depends on the background prevalence of H. pylori infection. Thus, if H. pylori is highly prevalent in the population, a negative test is more likely to be a false negative while if H. pylori is rare in the population, a positive test is more likely to be a false positive. These types of practical difficulties can impair the value of non-invasive H. pylori tests.54

The British Society of Gastroenterology has recommended that H. pylori testing be used to identify those with dyspepsia who should be referred for endoscopy.55 However, this option will still result in referral of approximately one-third of young dyspeptics who are H. pylori-positive. Moreover, in high H. pylori prevalence areas, this approach may result in a paradoxical increase in waiting lists for endoscopy.

As fear of serious disease and anxiety are key factors that drive health care seeking in dyspepsia,17[18]–19 management must address the issue of adequately reassuring patients. H. pylori testing probably provides adequate reassurance. Patel et al. evaluated H. pylori serology in the management of 183 young dyspeptic patients aged under 45 years.49 Of these, 70 were H. pylori-seronegative and had no alarm features. The remaining 113 patients (90 seropositive for H. pylori and 23 with alarm features) underwent endoscopy; 34 (19%) had an ulcer. All the patients had the nature of their clinical condition explained to them and were referred back to the care of their primary care physician; no difference was found in outcome between the two groups.

Cure of H. pylori infection does not cure the symptoms in all patients with peptic ulcer disease. There is a residual group of patients who continue to have symptoms or develop new symptoms.56 Earlier reports from Germany have suggested that up to 26% of patients with duodenal ulcer who have eradication of H. pylori develop reflux oesophagitis compared with 13% of duodenal ulcer patients with ongoing infection.57 However, this association remains controversial.58

The Working Party concludes that the benefits from cure of H. pylori peptic ulcer in patients with uninvestigated dyspepsia is sufficient to support the approach of testing and treatment, assuming that the prevalence of peptic ulcer disease in those with H. pylori infection continues to remain as high as is now reported in the literature.

MANAGEMENT OF FUNCTIONAL DYSPEPSIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

The principles of management include finding out why the patient with chronic symptoms has presented on this occasion, providing an adequate explanation of the likely pathophysiology, reassuring the patient that there is not serious underlying disease and removing potential precipitating factors (such as eliminating a high-fat diet or certain drugs). If medication is then required, it would be logical to apply therapy that is targeted to the likely underlying pathophysiological disturbance occurring in the individual patient. Based on the available literature, a clear link between pathophysiological disturbances and individual symptoms varies from nil to modest.59 Therefore, empirical therapy remains a mainstay approach in the management of functional dyspepsia.

Antisecretory therapy

The rationale for antisecretory drugs rests on the assumption that either acid secretion is disturbed or acid sensitivity is abnormal in the gastroduodenal region. H2-blockers have been most widely used in functional dyspepsia but the results of randomized controlled trials have been mixed.60[61][62][63]–64 Meta-analyses of selected studies suggested a 20% response over and above placebo but these were flawed because of the selective inclusion criteria applied.62, 63 An adequate meta-analysis has not been possible with these studies in large part because of the very variable symptom scoring approaches used.

Recent studies have evaluated the role of proton pump inhibitor therapy in functional dyspepsia.65, 66 Two large randomized controlled trials detected only a small overall therapeutic gain with omeprazole 20 mg over placebo (38% had complete symptom relief on omeprazole 20 mg daily compared with 28% on placebo).65 However, if patients were classified into symptom subgroups based on symptom predominance (as opposed to groupings of symptoms), then those who stated epigastric pain was their predominant complaint had a significantly better response to proton pump inhibitor therapy than those who identified epigastric discomfort (including early satiety, bloating and distension) as the predominant complaint.65 This suggests that a symptom classification, while not useful in uninvestigated dyspepsia, may be of some value in helping to identify symptom responders to antisecretory therapy.

There is no evidence that either basal or peak acid output is abnormal in patients with functional dyspepsia compared with controls.67 However, one study from Scotland using gastrin releasing peptide, which simulates the postprandial state, found that a subset of H. pylori infected patients with functional dyspepsia did have acid dysregulation with an acid output in the range found in patients with H. pylori infected duodenal ulcer disease.68 Despite these observations, large randomized controlled trials in patients with functional dyspepsia have failed to find that H. pylori status was linked to symptom response with proton pump inhibitor therapy,65 suggesting no clinically important relationship between acid dysregulation and H. pylori in this disorder.

Why a subset should respond to acid suppression therefore remains unclear. Undiagnosed atypical gastro-oesophageal reflux disease is one explanation.3, 4, 69[70]–71 Another is the possibility of an acid sensitive stomach or duodenum in a subset of patients with functional dyspepsia. The data for gastric sensitivity to acid is very limited with one study suggesting that there was no clear pattern of response to acid compared with saline infusion into the stomach.72 On the other hand, an uncontrolled study of duodenal sensitivity suggested that patients with dyspepsia could be clearly discriminated from controls based on acid infusion into this region.73

Prokinetic therapy

Prokinetics have been successfully applied in functional dyspepsia but benefits are relatively modest. Domperidone is a dopamine type 2 receptor antagonist. In 11 small trials, 10 showed a significant benefit of domperidone over placebo.62[63]–64 Cisapride is a partial 5HT4-receptor agonist. There have been 19 trials with cisapride, and 15 have shown that this drug was superior to placebo.62[63]–64, 74 A recent meta-analysis suggested that cisapride resulted in an approximately twofold increase in therapeutic response over and above placebo in functional dyspepsia, but many of the studies were methodologically weak,74 confirming other reports.62, 63

How prokinetics may promote symptom relief in functional dyspepsia remains unclear. A direct association between symptom response and accelerated gastric emptying has not been clearly demonstrated although admittedly this has been poorly studied.75 Tack et al. showed recently that cisapride did enhance meal induced fundic relaxation which is impaired in a subset of patients with functional dyspepsia, and this may be a key observation.76 Interestingly, cisapride did not lower discomfort thresholds to gastric distension and therefore any benefit is unlikely to be explained by a visceral analgesic effect.76

Treatment of H. pylori

The majority of patients with uninvestigated dyspepsia have functional dyspepsia, thus if it were shown that a subset of these patients who had H. pylori infection had symptom benefit from eradication then this would further strengthen the case for H. pylori testing and treatment in all cases. A number of trials have been reported but older studies contained serious flaws.77 A meta-analysis concluded that there is a small benefit but this study was limited by exclusion of the majority of trials.78 However, recently a number of large, well conducted randomized controlled trials with adequate follow-up have been reported, which are summarized in Table 2.79[80][81]–82 These studies suggest that while it is still possible that a small sub-group of patients with functional dyspepsia are indeed responders, overall there is a no clinically significant benefit over placebo during one year of follow-up.83 Longer term follow-up is not, as yet, available.

Table 2.  . Double-blind randomized controlled trials with ≥ 12 months follow-up assessing eradication of H. pylori in functional dyspepsia Thumbnail image of

Excluding gastro-oesophageal reflux disease

Approximately 20% of patients with a diagnosis of functional dyspepsia will have pathological acid reflux if 24 h oesophageal pH testing is conducted. In the remainder where oesophageal exposure lies within the conventional normal range, a further subset have a link between their symptoms and reflux episodes.3 However, the exact size of this sub-group remains unclear as patient selection and symptom recording has not been optimal in the studies to date.71

In view of these findings, a therapeutic trial with high-dose proton pump inhibitor has potential clinical utility in the management of dyspepsia. The predictive value of such a proton pump inhibitor test for reflux disease may be reasonably good, based on the limited data available, but the patients selected have usually had chronic reflux symptoms.84 In dyspeptic patients who are H. pylori-negative and who are not taking NSAIDs (hence peptic ulcer disease is very unlikely), an empirical trial with high-dose acid suppression may be of most diagnostic value but this remains to be firmly established.

Resistant functional dyspepsia

The management of the patient with resistant dyspeptic symptoms continues to be a challenge. There are a paucity of controlled trials of antidepressants or behavioural therapies in functional dyspepsia. One controlled trial of relaxation therapy indicated that this was superior to standard care at 12 weeks, but no other data are available.85 A single study of psychotherapy was also promising.86 The tricyclic antidepressants and selective serotonin re-uptake inhibitors anecdotally appear to be of some benefit in patients with resistant symptoms but no adequate controlled trials are available to guide management. Mertz et al. in a very small study reported patient improvement with low-dose amitryptiline but this was not associated with normalization of the perceptual response to gastric balloon distention or sleep arousal.87

New visceral analgesics are under development but their clinical applicability is largely unknown. The kappa opioid agonist fedotozine has been shown in two large trials to produce statistically significant improvement in symptoms88, 89 but clinical significance was very unimpressive.90 Other visceral analgesics include the serotonin receptor type 3 antagonists which do not yet have an established role in functional dyspepsia.91

Data are accumulating that link specific symptoms with some pathophysiological disturbances, such as early satiety and impaired fundic relaxation,92 or severe fullness and vomiting and delayed gastric emptying.93 In addition, new and more potent compounds that selectively target such abnormalities are in development, and hence more successful therapy may become available in well-defined subsets of patients in the future.

CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

A number of guidelines for the management of dyspepsia have been proposed recently. The Maastricht consensus report advised H. pylori testing and treatment for young dyspeptic patients (under 45 years) without alarm features although opinion was not unanimous, with one-third voting uncertain; the strength of evidence was considered equivocal 22 The American Digestive Health Foundation in 1997 suggested that young patients under the age of 50 years with uninvestigated dyspepsia could either be tested for H. pylori or endoscoped, but no specific guidelines were proposed.21 The Asian Pacific Consensus meeting for the management of H. pylori recommended that in young patients without alarm features, H. pylori testing and treatment was appropriate in countries where the incidence of gastric cancer is low and appropriate testing and treatment is available,23 although in another report a brief trial of empirical therapy was recommended before embarking on H. pylori testing in order to try and avoid over-treating H. pylori in high prevalence regions.94 The American Gastroenterological Association guidelines for the management of dyspepsia recommended a H. pylori test-and-treat approach in the United States.13

Decision analyses and clinical trials

A number of decision analyses have been conducted in view of current management uncertainties. However, these models are by necessity somewhat artificial and the results have varied depending on the assumptions made. In general, decision analyses support the H. pylori test-and-treat strategy as the most cost effective approach for the management of uninvestigated dyspepsia.95, 96 However, the cost effectiveness of testing and treating for H. pylori decreases as the cost of endoscopy falls or the probability of symptom recurrence rises.47, 95 Depending on the assumptions, others have found that any differences in costs may take years to accrue and differences are minimal,97 particularly if H. pylori treatment is not efficacious in functional dyspepsia.98

Preliminary reports of clinical trials comparing a test-and-treat strategy with endoscopy have recently become available. Four studies have reported that a H. pylori test-and-treat strategy is safe and the clinical outcome is generally similar to an endoscopic strategy.99[100][101]–102 It is a major strength of these clinical trials that they have come to similar conclusions, confirming the predictions made by the decision analyses, even though they used different randomization procedures and were conducted in different settings. The major negative outcome in the largest of these studies101 was a modestly lower patient satisfaction in the test and treat strategy. The unsatisfied patients were mainly H. pylori-negative patients who were not offered an endoscopy. Outside the rigid frameworks of a clinical trial such patients may threaten the overall cost-effectiveness in the long term if they continue to consume health care resources by visiting doctors and undergoing additional diagnostic testing. The studies were performed in very similar health care systems in Europe (Denmark and the UK) and the results may not translate to different cultures. Furthermore, the outcome may depend on the H. pylori prevalence in the community and in particular on the prevalence of peptic ulcer in H. pylori-negative dyspeptic patients. Notably, the test-and-treat trials have been conducted in communities where the prevalence of H. pylori in those with dyspepsia is 30–50%, and among infected persons 40–60% have had an ulcer. As the prevalence of H. pylori and associated ulcers declines in the future in Western nations, the strategy may no longer provide the same benefit.

WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

The Working Party recommends the following strategy for management of uninvestigated dyspepsia (Figure 1). In those with new onset dyspepsia or for first time presenters with dyspepsia, it is worthwhile subdividing patients into those with and without alarm features. Alarm features include an age threshold (arbitrarily set at age 50 years in Western countries but varying depending on the country-specific incidence of gastric cancer), specific symptoms and signs, and chronic NSAID use which cannot be ceased. Those with alarm features should undergo prompt endoscopy whenever possible. This strategy, whilst likely to be cost effective, implies that early (and hence curable) gastric cancers in young persons will be missed initially, albeit very rarely in Western countries. Gastric biopsies are recommended to document H. pylori status. In those with H. pylori infection and a normal endoscopy, treatment may be offered on a case-by-case basis but patients should be advised of the potential advantages and disadvantages of therapy. Advantages may include symptom relief in a small minority and prevention of future peptic ulcer disease and non-cardia gastric adenocarcinoma, although this is not proven.103 Disadvantages theoretically might include the development of gastro-oesophageal reflux disease and the development of cardia cancer, but these possibilities remain highly contentious.58 The Working Party concluded, based on the available evidence, that the benefits of treatment of H. pylori in functional dyspepsia probably outweigh the risks.

image

Figure 1. . Management of dyspepsia in western nations. GERD=gastro-oesophageal reflux disease; IBS=irritable bowel syndrome. + Younger age cut-offs in countries with a high incidence of gastric cancer. * Provisional diagnosis peptic ulcer disease (but majority have functional dyspepsia). ** Provisional diagnosis functional dyspepsia.

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In countries where prompt endoscopy is neither affordable nor available, empirical management remains the only option (which may include antisecretory or prokinetic therapy initially, and in regions with a high background prevalence of H. pylori infection, anti-H. pylori therapy without testing).23

In dyspepsia without alarm features, patients who have had symptoms for less than 4 weeks can be managed initially with reassurance and over-the-counter medications (e.g. antacids or low-dose H2 antagonists). The 4-week threshold is arbitrary and based on the clinical judgement of the Working Party. More potent antisecretory therapy is not recommended based on best clinical practice because of the risk of inappropriately healing peptic ulcer disease, which may lead to the next presentation being serious (e.g. bleeding or perforation).

In those with symptoms for 4 weeks or longer or a history of recurrent symptoms who do not require prompt endoscopy, more specific approaches are indicated. In general, H. pylori testing and treatment is recommended as the next step because of the risk of peptic ulcer disease in infected patients. Symptoms appear to be neither sensitive nor specific enough to be applied to try and identify those who are likely to have peptic ulcer disease, in contrast to H. pylori testing. The urea breath test is considered the optimal non-invasive test to use and the Working Party recommends this test be made much more widely available. In the absence of breath testing or if this option is not affordable, a locally validated serological test with a sensitivity and specificity of at least 90% is the next best alternative;23 the lack of adequate local validation may mean, however, that the clinician is more often misled. Optimally, patients treated for H. pylori will have a follow-up breath test to confirm cure and this will help guide subsequent management. In patients who fail H. pylori treatment but are found to have been cured of the infection by urea breath testing, it is reasonable to label them as having a provisional diagnosis of functional dyspepsia and treat them with appropriate empirical antisecretory or prokinetic therapy. A strategy of H. pylori testing and referring positive patients for endoscopy is considered to be a less cost effective strategy. It was not considered appropriate to endoscope symptom failures after successful H. pylori treatment as the yield from endoscopy in this setting is likely to be extremely low unless alarm features have developed.

In H. pylori-negative patients with 4 weeks or more of dyspepsia, the likely clinical diagnosis is functional dyspepsia, although atypical gastro-oesophageal reflux disease also needs to be considered. While lifestyle modifications in functional dyspepsia such as a low-fat diet, small frequent meals, stopping smoking, reducing alcohol, reducing caffeine, avoiding irritating food stuffs and maintaining ideal weight are often recommended, there is no evidence that this approach is truly efficacious, although similar considerations apply in gastro-oesophageal reflux disease. Treatment options are either a proton pump inhibitor test for reflux (e.g. double dose proton pump inhibitor for 2 weeks) or empirical therapy with standard doses of an antisecretory or a prokinetic agent for 1 month. As the predictive value of high-dose proton pump inhibitor usage as a diagnostic test in this setting is as yet unavailable, the Working Party supports the concept of standard dose empirical therapy.

There is accumulating evidence suggesting that subdividing patients based on their predominant symptom complaint may be helpful in planning management at this stage, despite their lack of value in identifying structural disease in uninvestigated dyspepsia. Those who have ulcer-like dyspepsia (where epigastric pain is a predominant complaint rather than discomfort) are more likely to benefit from potent antisecretory therapy than those who have dysmotility-like dyspepsia (where epigastric discomfort, which includes bloating, fullness, early satiety or nausea rather than pain is a predominant complaint). If successful, treatment should be stopped after 4 weeks; therapy can be re-instituted for short periods if symptoms relapse, without the need for investigation unless alarm features develop. If after 4 weeks of standard empirical therapy the patient has failed to respond, then switching to an alternative drug class (e.g. from a prokinetic to an antisecretory) for up to 4 weeks is the next reasonable step. If this fails and patients have not yet undergone endoscopy, then this can be considered but is not essential. Although the yield of endoscopy will be low, this will ensure that patients with undiagnosed gastric cancer or reflux oesophagitis are detected and management changed appropriately. A delay of 8 weeks is unlikely to reduce the cure rate of gastric cancer in the view of the Working Party. Endoscopy may also help provide firm patient reassurance. Other testing depends on the clinical setting, but the history should be reviewed to ensure that another diagnosis is not being over looked (e.g. pancreatico-biliary disease or a drug side-effect).

In those with a likely diagnosis of functional dyspepsia who continue to then be symptomatic, treatment options are more limited but include behavioural therapy, a trial of antidepressant treatment or prescription of a visceral analgesic if available.

In developing countries or other regions with a high prevalence of H. pylori and very limited health care access, the management needs to be modified accordingly. The Working Party here endorses the recommendations of the Asia Pacific Consensus Conference23 (Figure 2). Initially it is suggested that an affordable antisecretory be prescribed for all patients (an indirect ‘ulcer test’) as referral for endoscopy even for older subjects is not a realistic option. If symptoms resolve no further treatment is required. However, if symptoms relapse or do not respond to initial treatment, then empirical H. pylori treatment is recommended without recourse to testing (as access to accurate testing is not usually available because of cost, most are infected and this group is presumably more likely to have peptic ulcer disease). If symptoms continue, referral for endoscopy if available is recommended at this time point, in order to ration this resource. This strategy will be superior to antisecretory therapy alone in eliminating ulcer disease but will of course miss gastric cancers, although most of these would be incurable anyway.

image

Figure 2. . Management of dyspepsia in regions with a high prevalence of H. pylori but limited access to endoscopy, H. pylori testing and expensive medications. Adapted from Ref. 23 with permission. * Provisional diagnosis peptic ulcer disease.

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CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References

It remains to be definitely shown that it is truly more cost effective to test and treat for H. pylori infection first rather than applying other management approaches. However, based on current evidence this appears to be the strategy of choice in young otherwise healthy patients with dyspepsia. In older patients or those with alarm features, prompt endoscopy should be the first step in management if available.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SYMPTOM PATTERNS TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  5. ALARM FEATURES TO IDENTIFY STRUCTURAL DISEASE IN UNINVESTIGATED DYSPEPSIA
  6. PROMPT ENDOSCOPY
  7. EMPIRIC THERAPY
  8. TESTING FOR H. PYLORI
  9. MANAGEMENT OF FUNCTIONAL DYSPEPSIA
  10. CONSENSUS OPINIONS ON MANAGEMENT OF DYSPEPSIA
  11. WORKING PARTY RECOMMENDATIONS FOR THE MANAGEMENT OF UNINVESTIGATED AND FUNCTIONAL DYSPEPSIA
  12. CONCLUSIONS
  13. ACKNOWLEDGEMENTS
  14. References
  • 1
    Talley NJ, Colin-Jones D, Koch KL, Koch M, Nyren O, Stanghellini V. Functional dyspepsia: a classification with guidelines for diagnosis and management. Gastroenterol Int 1991; 4: 145 60.
  • 2
    Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990; 335: 205 8.
  • 3
    Small PK, Loudon MA, Waldron B, Smith D, Campbell FC. Importance of reflux symptoms in functional dyspepsia. Gut 1995; 36: 189 92.
  • 4
    Talley NJ. Dyspepsia and heartburn: a clinical challenge. Aliment Pharmacol Ther 1997; 11(Suppl. 2): 1 8.
  • 5
    Armstrong D. Helicobacter pylori infection and dyspepsia . Scand J Gastroenterol 1996; 31(Suppl. 215): 38 47.
  • 6
    Johnsen R, Bernersen B, Straume B, Forde OH, Bostad L, Burhol PG. Prevalences of endoscopic and histological findings in subjects with and without dyspepsia. Br Med J 1991; 302: 749 52.
  • 7
    Richter JE. Dyspepsia: organic causes and differential characteristics from functional dyspepsia. Scand J Gastroenterol 1991; 182(Suppl): 11 16.
  • 8
    Heikkinen M, Pikkarainen P, Takala J, Rasanen H, Julkunen R. Etiology of dyspepsia: four hundred unselected consecutive patients in general practice. Scand J Gastroenterol 1995; 30: 519 23.
  • 9
    Nyren O, Adami HO, Gustavsson S, Lindgren PG, Loof L, Nyberg A. The ‘epigastric distress syndrome’. A possible disease entity identified by history and endoscopy in patients with nonulcer dyspepsia. J Clin Gastroenterol 1987; 9: 303 9.
  • 10
    Heikkinen MT, Pikkarainen PH, Takala JK, et al.Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997; 15: 82 6.
  • 11
    Klauser AG, Voderholzer WA, Knesewitsch PA, et al. What is behind dyspepsia? Dig Dis Sci 1993; 38: 147 54.
  • 12
    Talley NJ & Phillips SF. Non-ulcer dyspepsia: Potential causes and pathophysiology. Ann Intern Med 1988; 108: 865 79.
  • 13
    Talley NJ, Silverstein M, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA Technical Review – evaluation of dyspepsia. Gastroenterology 1998; 114: 582 95.
  • 14
    Lindell GH, Celebioglu F, Graffner HO. Non-ulcer dyspepsia in the long-term perspective. Eur J Gastroenterol Hepatol 1995; 7: 829 33.
  • 15
    Talley NJ, McNeil D, Hayden A, Colreavy C, Piper DW. Prognosis of chronic unexplained dyspepsia. A prospective study of potential predictor variables in patients with endoscopically diagnosed nonulcer dyspepsia. Gastroenterology 1987; 92: 1060 6.
  • 16
    Haug TT, Wilhelmsen I, Ursin H, Berstad A. What are the real problems for patients with functional dyspepsia? Scand J Gastroenterol 1995; 30: 97 100.
  • 17
    Lydeard S & Jones R. Factors affecting the decision to consult with dyspepsia: comparison of consulters and non-consulters. J R Coll Gen Pract 1989; 39: 495 8.
  • 18
    Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement and satisfaction with care. J Fam Pract 1997; 44: 281 8.
  • 19
    Talley NJ, Boyce P, Jones M. Dyspepsia and health care seeking in a community: How important are psychological factors? Dig Dis Sci 1998; 43: 1016 22.
  • 20
    American College of Physicians. Endoscopy in the evaluation of dyspepsia. Ann Intern Med 1985; 102: 266 9.
  • 21
    Howden CW. For what conditions is there evidence-based justification for treatment of Helicobacter pylori infection? Gastroenterology 1997; 113(Suppl. 6): S107 12.
  • 22
    Malfertheiner P, Megraud F, O’Morain C, et al.Current European concepts in the management of Helicobacter pylori infection – the Maastricht Consensus report. Eur J Gastroenterol Hepatol 1997; 9: 1 2.
  • 23
    Lam SK & Talley NJ. Report of the 1997 Asia Pacific Consensus Guidelines on the Management of H. pylori. J Gastroenterol Hepatol 1998; 13: 1 12.
  • 24
    Hunt RH & Thompson ABR. Canadian Helicobacter pylori consensus conference. Can J Gastroenterol 1998; 12: 31 41.
  • 25
    Colin-Jones DG, Bloom B, Bodemar G, et al.Management of dyspepsia. Report of a Working Party. Lancet 1988; 1: 576 9.
  • 26
    Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ III Dyspepsia and dyspepsia subgroups: a population based study. Gastroenterology 1992; 102: 1259 68.
  • 27
    Talley NJ, Weaver AL, Tesmer DL, Zinsmeister AR. Lack of discriminant value of dyspepsia subgroups in patients referred for upper endoscopy. Gastroenterology 1993; 105: 1378 86.
  • 28
    Mann J, Holdstock G, Harman M, et al.Scoring system to improve cost effectiveness of open access endoscopy. Br Med J 1983; 287: 937 40.
  • 29
    Crean GP, Holden RJ, Knill-Jones RP, et al.A database on dyspepsia. Gut 1994; 35: 191 202.
  • 30
    Lindberg G, Seensalu R, Nilsson LH, et al.Transferability of a computer system for medical history taking and decision support in dyspepsia. A comparison of indicants for peptic ulcer. Scand J Gastroenterol 1987; 22(Suppl. 128): 190 6.
  • 31
    Bytzer P & Schaffalitzky de Muckadell OB. Prediction of major pathologic conditions in dyspeptic patients referred for endoscopy. A prospective evaluation of a scoring system. Scand J Gastroenterol 1992; 27: 987 92.
  • 32
    Bytzer P, Hansen JM, Havelund T, et al.Predicting endoscopic diagnosis in the dyspeptic patient. The value of clinical judgement. Eur J Gastroenterol Hepatol 1996; 8: 359 63.
  • 33
    Bytzer P, Hansen JM, Schaffalitzky de Muckadell OB, Malchow-Moller A. Predicting endoscopic diagnosis in dyspeptic patients. The value of predictive score models. Scand J Gastroenterol 1997; 32: 118 25.
  • 34
    Heading RC, Wager E, Tooley PJ. Reliability of symptom assessment in dyspepsia. Eur J Gastroenterol Hepatol 1997; 9: 779 81.
  • 35
    Williams B, Luckas M, Ellingham JH, Dain A, Wicks AC. Do young patients with dyspepsia need investigation? Lancet 1988; 2: 1349 51.
  • 36
    Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997; 41: 513 7.
  • 37
    Johannessen T, Petersen H, Kleveland PM, et al.The predictive value of history in dyspepsia. Scand J Gastroenterol 1990; 25: 689 97.
  • 38
    Bernersen B, Johnsen R, Straume B. Non-ulcer dyspepsia and peptic ulcer: the distribution in a population and their relation to risk factors. Gut 1996; 38: 822 5.
  • 39
    Adang RP, Vismans JF, Talmon JL, Hasman A, Ambergen AW, Stockbrugger RW. Appropriateness of indications for diagnostic upper gastrointestinal endoscopy: association with relevant endoscopic disease. Gastroint Endosc 1995; 42: 390 7.
  • 40
    Horrocks JC & De Dombal FT. Clinical presentation of patients with ‘dyspepsia’. Detailed symptomatic study of 360 patients. Gut 1978; 19: 19 26.
  • 41
    Gillen D & McColl KEL. Does concern about missing malignancy justify endoscopy in uncomplicated dyspepsia in patients aged less than 55? Am J Gastroenterol 1999; 94: 75 9.
    Direct Link:
  • 42
    Bytzer P, Hansen JM, Schaffalitzky de Muckadell OB. Empirical H2-blocker therapy or prompt endoscopy in management of dyspepsia. Lancet 1994; 343: 811 6.
  • 43
    Wiklund I, Glise H, Jerndal P, Carlsson J, Talley NJ. Does endoscopy have a positive impact on quality of life in dyspepsia? Gastrointest Endosc 1998; 47: 449 54.
  • 44
    Jones R. What happens to patients with non-ulcer dyspepsia after endoscopy? Practitioner 1988; 232: 75 6.
  • 45
    Sorbi D, Gostout CJ, Pasha T, Lindor KD. Small caliber esophago gastroduodenoscopy without sedation: a prospective study of healthy volunteers. Gastroint Endosc 1998; 47: AB40AB40.
  • 46
    Axon ATR. Chronic dyspepsia: who needs endoscopy? Gastroenterology 1997; 112: 1376 80.
  • 47
    Silverstein MD, Petterson T, Talley NJ. Initial endoscopy or empirical therapy with or without testing for Helicobacter pylori for dyspepsia: a decision analysis. Gastroenterology 1996; 110: 72 83.
  • 48
    McColl KEL, El-Nujumi A, Murray L, et al.The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients. Gut 1997; 40: 302 6.
  • 49
    Patel P, Khulusi S, Mendall MA, et al.Prospective screening of dyspeptic patients by Helicobacter pylori serology. Lancet 1995; 346: 1315 8.
  • 50
    Vaira D, Stanghellini V, Menegatti M, et al.Prospective screening of dyspeptic patients by Helicobacter pylori serology: a safe policy? Endoscopy 1997; 29: 595 601.
  • 51
    Fraser AG, Ali MR, McCullogh S, et al.Diagnostic tests for Helicobacter pylori –can they select patients for endoscopy? NZ Med J 1996; 109: 95 8.
  • 52
    Xia HH-X, Kalantar J, Ma Wyatt J, et al.Failure of Helicobacter pylori serology to identify most peptic ulcer disease in patients with dyspepsia. Gastroenterology 1998; 114: A336A336(Abstract).
  • 53
    Loy C, Irwig L, Katelaris PH, Talley NJ. Do commercial serological kits for Helicobacter pylori infection differ in accuracy?: a meta-analysis. Am J Gastroenterol 1996; 91: 1138 44.
  • 54
    Agreus L & Talley N. Challenges in managing dyspepsia in general practice. Br Med J 1997; 315: 1284 8.
  • 55
    Axon ATR, Bell GD, Jones RH, et al.Guidelines on appropriate indication for upper gastrointestinal endoscopy. Br Med J 1995; 310: 853 6.
  • 56
    Forbes GM, Glaser ME, Cullen DJ, et al.Duodenal ulcer treated with Helicobacter pylori eradication: seven-year follow-up. Lancet 1994; 343: 258 60.
  • 57
    Labenz J, Blum AL, Bayerdorffer E, Meining A, Stolte M, Borsch G. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112: 1442 7.
  • 58
    Xia HH-X & Talley NJ. Helicobacter pylori infection, atrophic gastritis and reflux esophagitis: an unexplored triangle . Am J Gastroenterol 1998; 93: 394 400.
    Direct Link:
  • 59
    Talley NJ. Functional dyspepsia – Should treatment be targeted on disturbed physiology? Aliment Pharmacol Ther 1995; 9: 107 15.
  • 60
    Nyren O, Adami HO, Bates S, et al.Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. N Engl J Med 1986; 314: 339 43.
  • 61
    Talley NJ, McNeil D, Hayden A, Piper DW. Randomized, double-blind, placebo-controlled crossover trial of cimetidine and pirenzepine in nonulcer dyspepsia. Gastroenterology 1986; 91: 149 56.
  • 62
    Dobrilla G, Comberlato M, Steele A, Vallaperta P. Drug treatment of functional dyspepsia. A meta-analysis of randomized controlled clinical trials. J Clin Gastroenterol 1989; 11: 169 77.
  • 63
    Finney JS, Kinnersley N, Hughes M, Obrantear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroent 1998; 26: 312 20.
  • 64
    Holtmann G & Talley NJ. Functional dyspepsia. Current treatment recommendations. Drugs 1993; 45: 918 30.
  • 65
    Talley NJ, Meineche-Schmidt V, Pare P, et al.Efficacy of omeprazole in non-ulcer dyspepsia: a double-blind randomized placebo-controlled trial. Aliment Pharmacol Ther 1998; 12: 1055 65.
  • 66
    Jones RH & Baxter G. Lansoprazole 30 mg daily versus ranitidine 150 mg b.d. in the treatment of acid-related dyspepsia in general practice. Aliment Pharmacol Ther 1997; 11: 541 6.
  • 67
    Tucci A, Corinaldesi R, Stanghellini V, et al.Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992; 103: 768 74.
  • 68
    El-Omar E, Penman I, Ardill JE, McColl KE. A substantial porportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients. Gut 1995; 26: 534 8.
  • 69
    Shi G, Bruley des Varannes S, Scarpignato C, Le Rhun M, Galmiche JP. Reflux related symptoms in patients with normal oesophageal exposure to acid. Gut 1995; 37: 457 64.
  • 70
    Farup PG, Hovde O, Breder O. Are frequent short gastro-oesophageal reflux episodes the cause of symptoms in patients with non-ulcer dyspepsia responding to treatment with ranitidine? Scand J Gastroenterol 1995; 30: 829 32.
  • 71
    Talley NJ. H. pylori and dyspepsia. Yale J Biol Med 1999 in press.
  • 72
    George AA, Tsuchiyose M, Dooley CP. Sensitivity of the gastric mucosa to acid and duodenal contents in patients with non-ulcer dyspepsia. Gastroenterology 1991; 101: 3 6.
  • 73
    Joffe SN & Primrose JN. Pain provocation test in peptic duodenitis. Gastrointest Endosc 1983; 29: 282 4.
  • 74
    Veldhuyzen van Zanten S & Talley NJ. Cisapride for treatment of non-ulcer dyspepsia (NUD): a meta-analysis of randomized controlled trials. Gastroenterology 1998; 114: A323A323(Abstract).
  • 75
    Kellow JE, Cowan H, Shuter B, et al.Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995; 9: 153 60.
  • 76
    Tack J, Broekaert D, Coulie B, Janssens J. The influence of cisapride on gastric tone and perception of gastric distension. Aliment Pharmacol Ther 1998; 12: 761 6.
  • 77
    Talley NJ. A critique of therapeutic trials in Helicobacter pylori-positive functional dyspepsia . Gastroenterology 1994; 106: 1174 83.
  • 78
    Laheij RJF, Jansen JBMJ, Van De Lisdonk EH, Severens JL, Verbeek ALM. Review article: Symptom improvement through eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 1996; 10: 843 50.
  • 79
    Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in functional dyspepsia: randomized double-blind placebo-controlled trial with 12 months’ follow-up. BMJ 1999; 318: 833 7.
  • 80
    Gilvarry J, Buckley MJM, Beattie S, Hamilton H, O’Morain CA. Eradication of Helicobacter pylori affects symptoms in non-ulcer dyspepsia. Scand J Gastroenterol 1997; 32: 535 40.
  • 81
    McColl KEL, Murray LS, El-Omar E, et al.Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. NEJM 1998; 339: 1869 74.
  • 82
    Blum A, Talley NJ, O’Morain C, et al.Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. NEJM 1998; 339: 1875 81.
  • 83
    Bolling Sternevald E, Talley NJ, Blum AL et al. Does cure of Helicobacter pylori (Hp) improve symptoms in patients with functional dyspepsia? Am J Gastroenterol 1998; 93: 16501650 (abstract).
  • 84
    Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, et al.Omeprazole as a diagnostic tool in gastroesophageal reflux disease. Am J Gastroenterol 1997; 92: 1997 2000.
  • 85
    Bates S, Sjoden P, Nyren O. Behavioral treatment of non-ulcer dyspepsia. Scand J Behav Ther 1988; 17: 155 65.
  • 86
    Haug TT, Wilhelmsen I, Svebak S, Berstad A, Ursin H. Psychotherapy in functional dyspepsia. J Psychosom Res 1994; 38: 735 44.
  • 87
    Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol 1998; 93: 160 5.
    Direct Link:
  • 88
    Read NW, Abitbol JL, Bardhan KD, Whorwell PJ, Fraitag B. Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia. Gut 1997; 41: 664 8.
  • 89
    Fraitag B, Homerin M, Hecketsweiler P. Double-blind dose–response multicenter comparison of fedotozine and placebo in treatment of nonulcer dyspepsia. Dig Dis Sci 1994; 39: 1072 7.
  • 90
    Talley NJ. Visceral analgesics and functional dyspepsia – have we found the Holy Grail? Gut 1997; 41: 717 8.
  • 91
    Maxton DG, Morris J, Whorwell PJ. Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia? Aliment Pharmacol Ther 1996; 10: 595 9.
  • 92
    Tack J, Piessevaux H, Coulie B, Caenepeal B, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115: 1346 52.
  • 93
    Stanghellini V, Tosetti C, Paternico A, et al.Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996; 110: 1036 42.
  • 94
    Talley NJ, Lam SK, Goh KL, Fock KM. Management guidelines for uninvestigated and functional dyspepsia in the Asia-Pacific region. J Gastroenterol Hepatol 1998; 13: 335 53.
  • 95
    Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Alternative treatment strategies for patients with suspected peptic ulcer disease. Ann Intern Med 1995; 123: 260 8.
  • 96
    Ofman JJ, Etchason J, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori-seropositive patients with dyspepsia: Clinical and economic consequences . Ann Intern Med 1997; 126: 280 91.
  • 97
    Briggs AH, Sculpher MJ, Logan RPH, Aldous J, Ramsay ME, Baron JH. Cost effectiveness of screening for and eradication of Helicobacter pylori in management of dyspeptic patients under 45 years of age . Br Med J 1996; 312: 1321 5.
  • 98
    Sonnenberg A. Cost-benefit analysis of testing for Helicobacter pylori in dyspeptic subjects. Am J Gastroenterol 1996; 91: 1773 7.
  • 99
    Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial for a test and treat policy versus gastroscopy in young H. pylori positive dyspeptic patients. Gut 1998; 42(Suppl. 1): A17A17(Abstract).
  • 100
    Jones RH, Tait CL, Sladen G, Weston-Baker J. A Helicobacter test and treat strategy: costs and outcomes in a randomised controlled trial in primary care . Gut 1998 42(Suppl. 1): A81A81(Abstract).
  • 101
    Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. H. pylori test and treat or prompt endoscopy for dyspeptic patients in primary care. A randomized controlled trial of two management strategies: one year follow-up. Gastroenterology 1998; 114: A196A196(Abstract).
  • 102
    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. Gut 1998; 42(Suppl. 1): A82A82(Abstract).
  • 103
    Axon A & Forman D. Helicobacter gastroduodentitis – a serious infectious disease: antibiotic treatment may prevent deaths in decades ahead. Br Med J 1997; 314: 1430 1.