Optimizing Evaluation and Treatment Strategies in Acid-Related Disorders
Eamonn M. M. Quigley, MD

Symptomatic Heartburn and Functional Dyspepsia: Introduction to Terminology

Slide 1. Optimizing Evaluation and Treatment Strategies in Acid-Related Disorders


Slide 2. I am going to address 2 of the 3 most challenging clinical disorders in the upper gastrointestinal (GI) tract, symptomatic heartburn and functional dyspepsia.


Slide 3. When you look at the clinical manifestations of gastroesophageal reflux disease (GERD), you can look at it from 3 perspectives: symptoms, mucosal appearances, and complications.

Looking first at symptoms, it is clear from many studies that the most specific and sensitive symptoms for the diagnosis of GERD are heartburn and acid regurgitation. However, it is equally clear that many patients with these symptoms do not have erosive esophagitis; they have symptomatic reflux disease.

Atypical symptoms are clearly related to reflux, or have been proposed as being related to reflux; they are vast. The best defined symptoms are noncardiac chest pain, hoarseness or reflux laryngitis, chronic cough, asthma, pulmonary fibrosis, hiccups, and dental erosion. There are many others.

In terms of complications: esophageal erosion and/or ulcer; strictures; Barrett's esophagus; and the most dreaded complication of all, esophageal adenocarcinoma.


Slide 4. My remit is to address the issue of symptomatic GERD. This is certainly a diagnosis in evolution. Here we have listed 3 of the most commonly employed definitions of symptomatic GERD, also referred to by some as nonerosive reflux disease (NERD) or endoscopy-negative reflux disease (ENRD).

The first one defined symptomatic reflux disease as existing when conditions satisfy the definition of reflux disease, but the patient does not have Barrett's esophagus or definite endoscopic esophageal breaks. Alternately, it has been defined as burning, retrosternal discomfort for at least 3 months with a normal esophageal mucosa, or as typical symptoms of reflux disease caused by intraesophageal acid in the absence of visible esophageal mucosal injury. These definitions are saying that you have a patient with symptoms that appear to be related to acid exposure, but in whom conventional endoscopy fails to demonstrate any mucosal abnormality.


Symptomatic Gastroesophageal Reflux Disease

Slide 5. Symptomatic reflux disease is very common. This study from London found that over 50% of endoscoped patients had either a normal mucosa or erythema, a finding that nowadays would be regarded as within the range of normal.


Slide 6. This has been replicated in several other studies, with the prevalence of symptomatic GERD varying from 49% to 71% in these 3 studies. Clearly, this is the major manifestation of reflux disease in the community.


Slide 7. Symptoms do not help predict the patient who will have a normal mucosa from the patient who will have erosive esophagitis. This complex diagram looked at some of the primary symptoms of reflux disease as well as some other symptoms. Here the prevalence of all of the symptoms -- whether it be heartburn and regurgitation or more atypical symptoms, such as nausea and epigastric pain -- are equally common in patients who have a normal mucosa and who have so-called symptomatic reflux disease.


Slide 8. Similarly, the severity of symptoms -- particularly the cardinal symptom of reflux, heartburn -- is identical in patients with or without erosive esophagitis. So neither the pattern of symptoms nor the severity of symptoms can predict who will have esophagitis or who will have a normal mucosa.


Slide 9. However, the importance of symptomatic reflux disease or NERD lies in the fact that regardless of the pathology, it results in a significant impairment in quality of life. In this study, the impairment in quality of life was identical in patients who were endoscopy negative and endoscopy positive. It was correlated not with pathology, but with the severity of symptoms, which makes sense.


Slide 10. When we look in more detail at the patient with heartburn and a normal endoscopy, it is clear that we can divide them into subgroups based on some commonly available physiological studies.

In the first group, which may represent about 50% of patients with symptomatic reflux disease or NERD, about 50% will have abnormal exposure on a 24-hour pH study. In other words, the total time their pH was less than 4 will be above the normal range. However, about 50% will have normal acid exposure. Among them, there would be a group of patients who, when you look at symptom reflux correlations, have a clear and statistically significant correlation between symptoms and acid events, or referred to as a sensitive esophagus. This represents, perhaps, one third of the patients who have normal acid exposure.

You're left with the group of patients who have heartburn and whose symptoms are similar to other patients with proven reflux disease, but who have a normal acid exposure and no symptom reflux correlation, so-called nonacid related heartburn, referred to by others as functional heartburn. These patients are a very challenging group to deal with.


Slide 11. There are some other issues with regard to pathophysiology in symptomatic heartburn patients. They have a lower incidence of primary peristaltic failure; their peristalsis is usually normal. Lower esophageal sphincter incompetence is less common in these patients. It is unusual to find a hiatal hernia and, as I described, esophageal acid exposure is often normal.

There have been very interesting recent studies showing that there are subtle abnormalities in morphology and physiology in the esophageal mucosa in these patients. There is increased paracellular permeability; and there is increased chemoreceptor sensitivity in the esophageal epithelium. It has been suggested that the increased paracellular permeability allows access to submucosal neurons for acid, which would not otherwise be possible and may, therefore, explain how these patients become symptomatic.

More recently there have been several interesting studies using magnification endoscopy, chromoendoscopy, and other techniques, which reveal a very subtle evidence of mucosal breaks in these patients. It has been suggested, for example, that the patients with abnormal acid exposure and a normal conventional endoscopy may have these subtle endoscopic findings; they may have microscopic esophagitis.


Empiric Therapy for Symptomatic Gastroesophageal Reflux Disease

Slide 12. What about management of these patients? If indeed these patients do not have esophagitis and if one accepts that their natural history is benign, then empiric therapy would appear to be a logical approach. This has been approached in 2 ways, first using empiric therapy as a diagnostic test, the proton pump inhibitor (PPI) test.

Here we have a series of studies that looked at the sensitivity of the PPI test in diagnosing symptomatic GERD. When you compare it with reflux in general, the sensitivity falls off significantly. It was quite a good test.


Slide 13. Here is the rationale for empiric therapy. In patients with symptomatic reflux disease you can normalize intraesophageal pH with PPI therapy. These studies have used rabeprazole in 2 doses and omeprazole in a dose of 20 mg. With rabeprazole you achieve normalization of esophageal pH in the vast majority of patients.


Empiric Therapy With Rabeprazole

Slide 14. This is due to the fact that with rabeprazole you obtain a very early onset of its effect and by day 1, for both nighttime and daytime heartburn, most of these patients are symptom free. It's particularly appropriate for this empiric approach.


Slide 15. In another study, looking at the response with 10 mg and 20 mg of rabeprazole, the time to the first 24-hour heartburn-free period was much shorter with these doses than with placebo. It was on average 2.5 and 3.5 days.


Slide 16. The same applied for the relief of nighttime heartburn.


Empiric Therapy With Proton Pump Inhibitors

Slide 17. How effective are PPIs in these patients? One of the interesting things is that the efficacy of PPIs may not be as impressive in patients with symptomatic heartburn as in patients with erosive esophagitis. The population with erosive esophagitis was those in whom all the original trials were performed because those trials used healing the esophagitis as a primary endpoint.

In this example with esomeprazole 20 mg and 40 mg, complete heartburn resolution at 4 weeks occurred in 34% and 33%, respectively, in the first study, or 42% and 36%, respectively, in the second study. These are the results that appear significantly lower than one would have expected in erosive esophagitis. In fact, this has been borne out in many other studies.

Proton pump inhibitors are effective in patients with symptomatic heartburn, but not as effective as one would expect in erosive esophagitis. This may, in part, reflect the heterogeneity of this group, which includes the group of patients who have neither abnormal acid exposure nor acid sensitivity.


Slide 18. This shows results with rabeprazole; very similar responses at 4 weeks, around 30% complete resolution of heartburn.


Slide 19. This compares the therapeutic gains over placebo for esomeprazole 40 mg and rabeprazole 20 mg, with very similar responses at 4 weeks.


Slide 20. One interesting observation, in one of the rabeprazole studies, was that rabeprazole seemed to have effects on some of the associated symptoms in these patients. There is a significant overlap between these symptomatic heartburn patients and patients with functional dyspepsia. It should be no surprise, therefore, that symptoms such as bloating, belching, and early satiety are very common. And in this study at least, there was a significant benefit not only for the typical symptoms, but also for these somewhat more dyspeptic-type symptoms among the patients who were randomized to receive rabeprazole in a dose of either 10 mg or 20 mg.


Slide 21. The other interesting point is that in patients who had failed omeprazole therapy, rabeprazole in a dose of 20 mg provided a significant improvement in both daytime and nighttime heartburn; again illustrating the superiority of second-generation PPIs.


Dyspepsia: Evaluating Treatment in Uninvestigated Dyspepsia

Slide 22. Let's move on to the other challenging area, that of dyspepsia. It is very important in any evaluation of the literature or abstracts in the area of dyspepsia to know exactly what population of dyspepsia is being defined, because here definitions do dictate outcome. Are we dealing with a group of patients that is uninvestigated? If that were the case, then you would expect that this would include not only patients with functional dyspepsia, but also patients with GERD and some with peptic ulcer disease. That will significantly alter the response to any of a variety of therapeutic agents.


Slide 23. A number of strategies have been evaluated and, in fact, utilized with uninvestigated dyspepsia. You could endoscope all patients. You could test for Helicobacter pylori and treat. You could test for H pylori; evaluate these patients with endoscopy; and then treat based on the endoscopic findings. You could provide empiric therapy, usually in the form of PPI, or in some cases even H pylori eradication, depending on background prevalence.


Slide 24. When we get to the patients who have been investigated, whether by endoscopy, H pylori serology, or both, you are now dealing with patients who fall into either organic dyspepsia, ie, peptic ulcer disease, or have true functional dyspepsia. This functional group is clearly very different from a nonselected group of patients with uninvestigated dyspepsia.


Dyspepsia: Evaluating Treatment in Functional Dyspepsia

Slide 25. Here we have several therapeutic options, including acid suppression, H pylori eradication, prokinetic therapy, etc.


Slide 26. It is very important, in evaluating therapeutic option, to remember the overlap that exists among these patients with symptomatic heartburn, NERD, and irritable bowel syndrome. The degree of overlap will influence the response to a therapeutic agent.


Slide 27. This is seen clearly in this particular study; when treated with a PPI, the response among patients with predominant heartburn in dyspepsia was significant. However it was insignificant in those dyspeptic patients who did not have predominant heartburn.


Slide 28. There are many possible sequelae of untreated H pylori infection.


Management of Dyspepsia: Helicobacter pylori Guidelines

Slide 29. In terms of H pylori, several guidelines have been developed. This is a summary of the various guidelines that have been developed. These guidelines suggest, for example, that in a low cancer prevalence community and at a young age, you should test and treat. If there's high cancer prevalence, you should do endoscopy and eradicate H pylori. If there's low cancer prevalence but an older age group, you should do endoscopy at an earlier stage.


Slide 30. This whole vexed issue of H pylori eradication in functional dyspepsia (as opposed to uninvestigated dyspepsia) remains a very fraught area. Expert meta-analyses have come to different conclusions. The Cochrane Library concludes that eradication is effective, which is considered as a holy grail of meta-analysis.


Slide 31. Proton pump inhibitors play an important role in H pylori eradication. There are some direct effects of PPIs on H pylori that improve eradication. They increase antibiotic concentration in gastric juice, and they increase permeability by decreasing viscosity of gastric juice. They also reduce degradation of acid-labile antibiotics in the stomach by increasing intragastric pH.


Slide 32. With that in mind, if we're going to include PPIs in a triple therapy regimen, and if we use newer PPIs that have a more rapid onset of action, might we be able to shorten the approved 10- to 14-day regimens? This obviously could improve compliance and reduce side effects, which closely predicts compliance and decrease cost of therapy.


Slide 33. It has been shown that by using shorter regimens, such as 7 days, you significantly improve the level of compliance over 10-day and 14-day regimens, in terms of dropout. It is because of discontinuation of therapy.


Helicobacter pylori Eradication Therapy

Slide 34. There are now increasing data to show that the shorter regimens -- this particular example is a 10-day regimen with a variety of combinations -- have very high eradication rates.


Slide 35. This is not influenced by whether or not patients have a past or present duodenal ulcer.


Slide 36. This looks at 7-day regimen vs 10-day regimen. This shows that there is no falloff in efficacy with the shorter regimen. However, when you go to 3 days, you do significantly lose efficacy, in terms of eradication rates.


Summary

Slide 37. In summary, I've attempted to highlight 2 of the more common problems in upper GI pathology: symptomatic heartburn and dyspepsia.

In symptomatic reflux disease, symptom relief is the issue. For this reason, PPIs with a rapid onset of action may well be preferred. In patients with functional dyspepsia, the PPI response reflects the overlap with GERD, especially patients with symptomatic reflux disease or NERD.

Regardless of the arguments about efficacy, there is certainly some evidence that H pylori eradication will benefit some patients with dyspepsia. For that reason, a rapid-onset PPI will allow for shorter-duration regimens, and may increase compliance. Therefore, it will significantly improve overall eradication rates.











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