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A SPECIAL ARTICLE

The Association and Clinical Implications of Gastroesophgeal Reflux Disease and H. pylori

Maxwell M. Chait

The relationship between GERD and H. pylori is complex and negatively associated with important implications for both individual patients and the nations of the world. Whereas the incidence of GERD and its complications, including Barrett’s and adenocarcinoma of the esophagus and gastric cardia have increased, the incidence of H. pylori related gastroduodenal and distal gastric adenocarci- noma has decreased in Western Europe and the United States. This suggests an inverse, negative, relationship between the two. H. pylori infection eradication does not cause GERD, but there is possibly a protective and negative effect of H. pylori in patients with GERD which is related to the virulence of the infecting strain and the distribution and severity of . It remains controversial whether or not to test and treat for the infection of H. pylori with respect to the direct management of GERD, because of its potentially protective effect. However, in patients who require long term therapy with PPI agents, a test and treat strategy may be appropriate, since PPI therapy might increase the risk of and its potential for B12 and gas- tric cancer in H. pylori infected individuals. If the prevalence of H. pylori decreases in the developing countries of the world, one may anticipate that there will be a decrease in incidence of cancer of the gastric body and antrum and an increase in the prevalence of GERD and incidence of adenocarcinoma of the esophagus and gastric cardia over the next few decades. This is an evolving area with important implications for individ- ual patients as well as for the nations of the world.

Maxwell M.Chait, M.D., F.A.C.P., F.A.C.G., Assistant Clinical Professor of Medicine, Columbia University College of Physicians and Surgeons, Hartsdale, New York.

40 PRACTICAL • JANUARY 2006 The Association and Clinical Implications of GERD and H. pylori

A SPECIAL ARTICLE

INTRODUCTION impairs the function of the LES and may impair the astroesophageal reflux disease (GERD) is the clearance of refluxed acid from the distal esophagus (7). most common upper gastrointestinal problem seen Reduction in esophageal acid clearance impaired by dis- Gin clinical practice. It is estimated that 10%–20% of turbances of esophageal motility and saliva production, adults have symptoms at least once weekly and delayed gastric emptying and duodenogastric reflux are 15%–40% have symptoms at least once monthly (1). also important factors. Although all ages are affected, the Complications of GERD vary from and elderly tend to have more severe complications of to Barrett’s esophagus and GERD (8). GERD is also associated with the develop- . In contrast, H. pylori infection is the ment of adenocarcinoma of the distal esophagus and gas- most common acquired factor in the etiology of gastri- tric cardia. The pre-malignant lesion for the development tis and ulcers of the and and in ade- of these cancers is Barrett’s esophagus. nocarcinoma of the body and antrum of the stomach (2). H. pylori is highly associated with gastritis and gas- Remarkably, as the prevalence of H. pylori and its com- troduodenal peptic ulcer disease. However, its effect on plications has declined in the industrialized nations of gastric acid depends upon the severity and distribution the world, the incidence of GERD and its complications of gastritis within the stomach, with either increased, have increased, suggesting a negative association decreased, or unchanged gastric acid secretion. In H. between the two disease states. H. pylori does not pre- pylori infection that is antrum predominant, there is dispose to GERD. In fact, evidence indicates a possible hypergastrinemia, gastric hypersecretion and the protective role. But, there is a higher incidence of propensity to gastroduodenal ulcer. All of the abnor- atrophic gastritis in patients taking proton pump malities resolve completely after eradication of the H. inhibitor (PPI) agents with H. pylori infection. There- pylori organism except for the increased maximal acid fore, the relationship between GERD and H. pylori is output in response to which remains unchanged complex and may have important implications for the in these patients (9). In contrast, patients with corpus individual patient as well as for the nations of the world. predominant infection tend to decreased gastric acid secretion which returns to normal with eradication of H. pylori. Basal gastric acid secretion is increased in PATHOPHYSIOLOGY OF GERD AND H. PYLORI subjects whose infection was eradicated, but not in GERD is predominantly a motility disorder. The abnor- those with persistent infection. However, basal and malities that appear to play a pathogenic role in GERD meal stimulated gastric acid secretion does not change are a defective antireflux barrier, abnormal esophageal after H. pylori eradication (10). Therefore, most studies clearance, reduced salivary production, altered suggest that patients with antrum predominant gastritis esophageal mucosal resistance, and delayed gastric emp- have increased gastric acid secretion that returns to nor- tying. Injury to the esophagus is due primarily to reflux mal after H. pylori eradication and patients with corpus of gastric acid and . In some cases, duodenogastric predominant gastritis have reduced gastric acid secre- reflux of bile may cause the injury (3). Nocturnal gas- tion that returns to normal after eradication (11). Addi- troesophageal reflux is associated with more severe man- tionally, H. pylori may influence the gastric acid con- ifestations and esophageal and extraesophageal compli- tent of the gastric refluxate and affect patterns of gas- cations of GERD (4–6). The lower esophageal sphincter tritis and gastric acid secretion by release of ammonia (LES) is the antireflux barrier. Abnormalities that make by H. pylori, which may partially neutralize gastric acid it dysfunctional promote acid reflux and the constellation (12). The amount of gastritis in the body of the stomach of GERD problems. The most common cause of reflux associated with lower gastric acidity returns to normal episodes is transient LES relaxations, the drop in LES when H. pylori is eradicated. Also, the hypergastrine- pressure not accompanied by swallowing. Multiple med- mia noted in these patients may lead to lower ications, such as nitrates, calcium channel blockers, ben- esophageal sphincter pressure (13). H. pylori, is associ- zodiazepines, anticholinergics, and antidepressants ated with the development of atrophic gastritis and ade- decrease LES pressure. The presence of a hiatal (continued on page 45)

PRACTICAL GASTROENTEROLOGY • JANUARY 2006 41 The Association and Clinical Implications of GERD and H. pylori

A SPECIAL ARTICLE

(continued from page 41) nocarcinoma of the body and antrum of the stomach. population has symptoms. (1) Also, the inci- Atrophic gastritis is associated with B12 malabsorption dence of GERD complications, especially adenocaci- and is a pre-malignant lesion for the development of noma of the esophagus, is rising. In contrast the preva- gastric cancer (2). Virulent strains of H. pylori, such as lence of H. pylori along with its of gastric the cag A+ strain are associated with increased devel- adenocarcinoma is steadily decreasing in these nations. opment of atrophic gastritis and gastric cancer (14,15). This is probably due to improvements in hygiene and No causal relationship between H. pylori infection socioeconomic factors and the treatment of H. pylori and gastroesophageal reflux disease has been demon- (23). Labenz, in a study of 6,125 patients with GERD, strated (16,17). However, H. pylori eradication may evaluated independent predictors of erosive disease, have a possible negative effect upon GERD. H. pylori including male gender, increased body mass, regular eradication effects on the development of GERD intake and duration of disease. He showed that would largely depend upon the patterns of gastritis and H. pylori had a protective effect in the subgroup analy- the disturbance of gastric acid secretion induced by the sis of patients with more severe Los Angeles C and D infection and could vary from individual to individual grade of esophagitis (24). Some studies have found that (18). For example, in patient’s with H. pylori antrum this negative association between H. pylori and GERD predominant infection, which is associated with is more marked with more virulent cagA+ strains of the increased acid secretion, eradication of the infection infection. In another study, however, Kuipers did not will lower acid secretion and may improve the GERD. observe a significant change in in patients On the contrary, if the infection is corpus predominant, with and without eradication of H. pylori in GERD which is associated with reduced acid secretion, treat- patients, although there was a trend towards reduced ment of the infection will result in increased acid control in the eradicated group (25). secretion which may induce or aggravate GERD. If H. H. pylori may have a possible protective effect, pylori infection produces no overall disturbance of especially the cagA+ strain, for the development of the acid secretion, then treatment of the infection is complications of GERD, including Barrett’s esophagus unlikely to have an effect on GERD (19). and adenocarcinoma of the esophagus and gastric cardia. Also, by treating H. pylori infection in a given pop- It is well known that complications of GERD are signif- ulation, the development or aggravation of GERD in icantly more frequent in Caucasian rather than in African that population will depend upon the pattern of H. American or Asian populations, which is inversely pro- pylori infection prevalent in that population. For exam- portional to the frequency of H. pylori infection. Several ple, studies from Asia, where H. pylori tends to be cor- studies have reported a negative association between the pus predominant and associated with lower gastric acid prevalence of H. pylori, especially the cagA+ strain, and secretion, show aggravation of esophagitis after H. the severe GERD complications of Barrett’s esophagus pylori treatment (19,20). However, studies from West- and esophageal adenocarcinoma, which suggests a pro- ern Europe and the United States, where there is no tective effect (26). A study from China revealed a step- regional preponderance of H. pylori infection, show wise relationship found between the increasing grade of conflicting results after H. pylori eradication (21,22). esophagitis and decreasing prevalence of H. pylori (27). A Swedish study showed that H. pylori was associated with a significantly decreased risk of adenocarcinoma of THE NEGATIVE RELATIONSHIP BETWEEN the esophagus (27). A subgroup analysis showed that the GERD AND H. PYLORI negative association was only apparent for the cagA+ There is a substantial body of epidemiologic evidence strains of H. pylori (28). that shows an inverse or negative association between the incidence of gastroesophageal reflux disease and H. pylori infection. The incidence of GERD in the indus- PROTON PUMP INHIBITORS AND H. PYLORI trialized countries of the Western world is quite high. The most common and effective way of treating For example, approximately 15%–40% of the adult U.S. patients with GERD is by suppressing gastric acid

PRACTICAL GASTROENTEROLOGY • JANUARY 2006 45 The Association and Clinical Implications of GERD and H. pylori A SPECIAL ARTICLE

secretion with proton pump inhibitor (PPI) agents. The As PPI agents change the H. pylori distribution to a degree of inhibition of gastric acid secretion and eleva- corpus predominant pattern, it has been postulated that tion of gastric pH that are achieved by PPI agents are they may accelerate the development of atrophic gastri- substantially greater in the H. pylori infected than unin- tis and potentially increase the risk of gastric cancer as fected patients and in H. pylori eradicated patients. For compared to uninfected patients. Virulent strains of H. example, in H. pylori infected patients, at pylori, such as cagA+, have been reported to cause a 20 mg per day produced a median gastric pH of 5.5. greater risk of developing atrophic gastritis and gastric After eradication of H. pylori, the pH fell to 3.0 (29). adenocarcinoma. Because of this potential threat of Wu demonstrated that H. pylori eradication was the increased gastric cancer in these patients, a test and treat only predictor of treatment failure in patients after strategy has been proposed by the Maastricht Consensus adjustments for age, sex, erosive esophagitis and hiatal Conference as well as by other investigators (35). How- hernia (30). Holtzman found that both the rate of heal- ever, PPI agents do not promote intestinal ing of endoscopically proven esophagitis and the rate of (36). Thus, it remains unclear if long term use of PPI resolution of symptoms was more rapid in the H. pylori agents in H. pylori infected patients poses a significant infected patients treated with PPI agents, as compared risk for the development of gastric cancer in later life. to H. pylori uninfected patients (31). Two mechanisms are likely to contribute to the enhanced potency of PPI agents in the presence of H. CONCLUSION pylori. PPI agents appear to transform the pattern of H. The relationship between GERD and H. pylori is com- pylori gastritis into a corpus predominant pattern of plex and negatively associated with important implica- gastritis, producing a marked increase in the inflam- tions for the individual and the populations of the world. mation in the acid secretion regions of the stomach The incidence of GERD and its complications, includ- which inhibits function and gastric acid ing adenocarcinoma of the esophagus, has increased in secretion. (32,33) This reduction of gastric acid sup- recent years, whereas the incidence of H. pylori related plements the pharmacological affect of PPI agents. In gastroduodenal peptic ulcer disease and distal gastric addition, ammonia produced by the H. pylori urease adenocarcinoma has decreased in the industrialized helps neutralize acid and thus contribute to the eleva- nations of the Western world, suggesting an inverse tion of intragastric pH. Although both effects are prob- relationship between the two. Current data demonstrate ably minor, the increased efficacy of PPI agents may that H. pylori infection eradication does not cause gas- be associated with improved symptom control and troesophageal reflux disease. However, there is possibly more rapid healing of esophagitis. a protective and negative association between H. pylori H. pylori infection has also been shown to affect the infection, especially the more virulent cagA+ strain, and level of gastric acid secretion after discontinuing PPI the development of GERD and its complications of Bar- therapy. For example, discontinuation of PPI therapy in rett’s esophagus and esophageal cancer that appears to some patients results in rebound hypersecretion of gas- depend upon the distribution and severity of the H. tric acid which continues for several months in H. pylori pylori gastritis. It remains controversial whether or not eradicated patients. This may be the result of a trophic to treat for the infection of H. pylori with respect to the affect of the elevated gastrin level during H. pylori direct management of GERD, because of its potentially infection that exerts a prolonged effect upon the parietal protective effect. However, in patients who require long cell mass. In contrast, some patients with H. pylori term therapy with PPI agents, a test and treat strategy infection did not show a significant rebound hyper- may be appropriate, since PPI therapy might increase secretion. This protective effect may be explained by a the risk of atrophic gastritis with its potential for B12 corpus predominant pattern of gastritis induced by PPI malabsorption and gastric cancer in H. pylori infected agents in H. pylori infected subjects that produces a per- individuals. This may be more important in patients sistent inhibition of gastric acid secretion after stopping from non-industialized countries and Asia where there the drug and prevents rebound acid hypersecretion (34). (continued on page 48)

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(continued from page 46) is a higher incidence of corpus predominant type of H. 17. Wu JC, Lai AC, Wong SK, et al. Dysfunction of oesophageal motil- ity in Helicobactor pylori infected patients with reflux oesophagitis. pylori infection. If this were to be the case, then one may Aliment Pharmacol Ther, 2001;15:1913-1919. anticipate an increased prevalence of GERD and its 18. Labenz J, Blum AL Bayerdorffer E, et al. Curing Helicobactor pylori infection in patients with duodenal ulcer may provoke reflux complications of Barrett’s esophagus and adenocarci- esophagitis. Gastroenterology, 1997;112:1442-1447. noma of the esophagus and gastric cardia in the devel- 19. Hamada H, Haruma K, Mihara M, et al. High incidence of relux oping countries of the world during the next few esophagitis after eradication therapy for Helicobactor pylori: impacts of and corpus gastritis. Aliment Pharmacol decades associated with a decreased prevalence of H. 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