Helicobacter pylori and Nonmalignant Diseases

Peptic Ulcer Disease

The relationship between H. pylori infection and peptic ulcer disease (PUD) and also peptic ulcer bleeding (PUB) has been extensively studied. A meta-analysis reported that the prevalence of PUD ranged worldwide between 0.1 and 4.7%, with an annual incidence ranging from 0.19 to 0.3% 1. The majority of studies have reported a decrease in the incidence and/or prevalence of PUD over time, presumably due to a decrease in H. pylori-associated PUD. H. pylori was initially responsible for up to 95% of all gastroduodenal ulcers, but more recent studies reported that the prevalence of H. pylori in patients with PUD ranged from 36 to 73%, depending on ethnicity, geographic, and socioeconomic factors 2.

A compilation of 71 original studies, including 8496 patients, found a mean 72% prevalence of H. pylori infection in PUB 3. The association between H. pylori infection and PUB was previously studied in a meta-analysis that confirmed that H. pylori infection increased the risk of ulcer bleeding (OR 1.79) 4. As a consequence of the introduction of potent acid inhibitors and eradication of H. pylori, a rapid decrease in both incidence and mortality of PUB was expected. However, although most studies confirm such a decrease, the rate of hospitalization because of PUB decreases only slowly5.

H. pylori resistance rates to antibiotics vary even in different regions of the same country. Effective H. pylori eradication reduces the rate of ulcer recurrence. Therefore, it is plausible that H. pylori eradication also prevents recurrence of ulcer bleeding. However, the efficacy of eradication for the prevention of recurrent bleeding from peptic ulcer has not been completely established. A prospective, long-term study included 1000 patients with previous PUB, 41% of them had previously used an NSAID and none received a PPI or NSAID during follow-up 6. Peptic ulcer rebleeding virtually did not occur after H. pylori eradication (0.5%). The authors concluded that maintenance of antisecretory therapy is not necessary if eradication is achieved. However, NSAID intake or H. pylori reinfection may exceptionally cause rebleeding in H. pylori-eradicated patients.

In daily clinical practice, concomitant H. pylori infection and NSAID and/or aspirin use are common, in particular, in elderly. Both H. pylori infection and NSAID use are independent risk factors for the development of PUD and associated bleeding. There is a synergistic effect for the development of GI bleeding when these factors are both present 7. Although H. pylori is frequently reported as a risk factor for upper GI bleeding in aspirin users, the real effect of H. pylori eradication on reducing the risk of bleeding remains unclear. The Maastricht guideline advocates an H. pylori test-and-treat strategy in aspirin users with a history of gastroduodenal ulcer because the long-term incidence of peptic ulcer bleeding is low in these patients after H. pylori eradication, even in the absence of gastroprotective treatment 7. Despite these findings, further studies are needed to confirm whether this strategy is a (cost-) effective therapy to reduce ulcer bleeding in high-risk aspirin users.

A prospective 10-year cohort study from Hong Kong assessed whether testing for H. pylori in aspirin users with a high ulcer risk would reduce the long-term incidence of ulcer bleeding 8. The investigators divided patients into three different cohorts. The first included H. pylori-positive aspirin users with a PUB history in whom H. pylori had been eradicated (n = 249). The second group consisted of H. pylori-negative aspirin users with a PUB history (n = 118). The third group, assigned as average-risk cohort, included aspirin users without a history of ulcers (n = 537). The incidence of ulcer bleeding (per 100 patient-years) in the H. pylori-eradicated cohort (OR 0.97; 95% CI 0.53–1.80) was similar to the average-risk cohort (OR 0.66; 95% CI 0.38–0.99). On the other hand, the H. pylori-negative cohort had a high incidence of recurrent bleeding (OR 5.22; 95% CI 3.04–8.96). This confirms that the long-term incidence of recurrent ulcer bleeding with aspirin use is low after H. pylori eradication despite a history of ulcer bleeding. Aspirin users without current or past H. pylori infection who develop ulcer bleeding, however, have a high risk of recurrent bleeding. Tests for H. pylori infection can be used to assign high-risk aspirin users to groups that require different gastroprotective strategies, in particular, patients with a positive test for H. pylori should receive anti-H. pylori therapy followed by confirmation of eradication. Their need for long-term gastroprotective therapy depends on the success of H. pylori eradication and concomitant use of drugs that can cause bleeding. However, H. pylori-negative patients should receive adequate gastroprotective co-therapy if they have a history of ulcer because they are prone to ulcer bleeding with aspirin use.

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a highly prevalent condition in the general population. Although it has previously been suggested that H. pylori eradication may cause both reflux symptoms and erosive esophagitis, the existence of such an association remains largely unsubstantiated.

A meta-analysis of 10 trials in which data of patients treated for H. pylori infection were compared to those receiving placebo concluded that the post-treatment incidence of reflux symptoms (17 vs 22.6%) and erosive esophagitis (5 vs 5.1%) was similar between both groups 9. A further subanalysis revealed a significantly lower incidence of GERD symptoms in the eradicated versus noneradicated group (13.8 vs 24.9%) (OR 0.55; 95% CI 0.35–0.87, p = .01). Overall, these data suggest that H. pylori eradication is not significantly associated with either reflux symptoms or erosive esophagitis onset, with some data actually suggesting an advantage in eradication in terms of a negative association with later development of GERD symptoms. One study showed a significant improvement in reflux disease-related quality of life scores one year after H. pylori eradication therapy 10. In another study from the United States, 1611 cases of an African–American population with esophagitis and/or gastritis and confirmed H. pylori status were included between 2004 and 2007 and compared with controls 11. The prevalence of H. pylori in gastritis patients was 40%, in esophagitis patients 4%, and in normal controls 34%. After adjusting for age and gender, the odds ratio of H. pylori infection in the esophagitis group versus the normal group was 0.06 (95% CI 0.01−0.59; p = .01). They concluded that H. pylori has a significant negative association with esophagitis in African–Americans, which may point to a protective role of H. pylori in the pathogenesis of esophagitis. In addition, another study on 2442 patients referred for upper gastrointestinal endoscopy observed H. pylori infection in 82% of GERD patients. A statistically significant relationship was found between H. pylori positivity and the grade of GERD 12. In line with these observations, the updated Maastricht consensus on management of H. pylori infection concluded that H. pylori status has no effect on symptom severity, symptom recurrence, and treatment efficacy in GERD 7. H. pylori eradication does not exacerbate pre-existing GERD nor affect treatment efficacy. Therefore, the presence of GERD should not dissuade to prescribe an H. pylori eradication treatment when otherwise indicated. Furthermore, long-term efficacy of PPI maintenance treatment for GERD is not influenced by H. pylori status 13.

Functional Dyspepsia

Functional dyspepsia (FD) is currently defined as symptoms of epigastric pain, epigastric burning, postprandial fullness, or early satiation, in the absence of any organic, systemic, or metabolic disease that is more likely to explain the symptoms 14. This chronic, relapsing and remitting disorder is commonly seen in individuals from all around the world. Data from a large population-based study demonstrated no effect on life expectancy and no differences in the numbers of gastrointestinal related deaths between subjects with or without dyspepsia 15.

The exact role of H. pylori in FD is still under debate. Some investigators have argued that if H. pylori gastritis is considered an organic disease, H. pylori-associated FD should not be considered as a functional disorder 16, 17.

Possible mechanisms by which H. pylori may elicit dyspeptic symptoms include alterations of gastric motility, as well as endocrine and acid-secretory abnormalities 18. Hunger sensations, acid secretion and gastrointestinal motility are regulated by ghrelin, particularly produced by the gastric enteroendocrine cell compartment 18. Gastric infection with H. pylori is associated with decreased ghrelin secretion 19. A study from China in fifty children with FD showed a significant increase in plasma ghrelin levels and gastric ghrelin mRNA expression after successful H. pylori eradication treatment 20. In contrast, no significant differences were found in children who did not achieve successful eradication. A small randomized clinical trial from Japan demonstrated an improvement of upper gastrointestinal symptoms in adult patients treated with “rikkunshito” (i.e., a traditional Japanese medicine) compared to patients treated with domperidone 21. The improvement of symptoms correlated with enhanced plasma ghrelin levels. Apart from the need for more trials on this topic, these findings may give insights in the underlying pathophysiology of FD symptoms.

Most guidelines recommend a test-and-treat strategy for H. pylori, especially in populations with a high H. pylori prevalence. However, the efficacy of this approach is limited, with a number to treat of 14 to achieve complete symptomatic response in one patient 22. It is becoming more clear that the role of H. pylori infection in FD differs between Western and Asian populations. H. pylori infection and related diseases are more common in Asia, and therefore considered as the major differential diagnoses of FD 23. Moreover, there is a trend of higher symptom response by H. pylori eradication treatment in Asian patients. Hence, particularly in these patients, exclusion of H. pylori infection is necessary before diagnosing FD. As in the past, current studies do not always give support for this statement. Sodhi et al. found no effect of H. pylori eradication on FD symptoms 24. In this trial from India, H. pylori-positive patients suffering from FD (Rome II criteria) were randomly allocated to triple therapy (n = 259) or PPI and placebo (n = 260) for 2 weeks. After a 12-month follow-up, no difference in symptom resolution was found between the triple therapy and placebo group (44 vs 37%, p = .13). It should be taken into account that despite the low eradication rate of 70%, all patients allocated to the triple therapy arm were included in the comparison, which may have influenced the outcome.

Asthma and Allergy

Helicobacter pylori is suggested to have not only pathogenic properties. Considered by some as a human commensal, H. pylori is thought to influence the development of the host immune system 25. Changes in our microbiota affected by altered ecological circumstances might explain the increasing prevalence of atopic diseases like asthma and allergy. H. pylori is a specific component of the human microbiome. In this context, several epidemiological studies showed an inverse relationship between H. pylori infection and asthma occurrence 26, but data are conflicting. Last year, two meta-analyses, both found a weak inverse association between asthma and H. pylori infection 27, 28. One study included cross-sectional, case-control, and cohort studies 27. Meta-analyses of pooled data from separate study types revealed a significant inverse association between H. pylori infection and asthma for cross-sectional studies only (OR 0.84; 95% CI 0.74–0.96). Discrepancies among pooled outcome of the study groups might be explained by differences in heterogeneity of study design, participants, and study quality. Stratification by age did not show a difference in trend between children and adults. No conclusions for children below age of 10 could be demonstrated, due to their low number in the analysis. The second meta-analysis was based on 14 studies, either with cross-sectional or case-control study design 28. Overall, a significant lower H. pylori infection rate was found in asthmatic participants (OR 0.84; 95% CI 0.73–0.96). Stratification to geographical region revealed that data from the United States determined this outcome, as studies from Asia and Europe did not show a significant inverse association. The prevalence of CagA-positive strains was similar in asthmatics and nonasthmatics. In both children and adults, an inverse but nonsignificant association between asthma and H. pylori infection was found.

Both meta-analyses in particular included adults rather than children. Therefore, more studies in children are needed for validation of the hypothesis that asthma is inversely associated with H. pylori infection.