Combination of Triple Therapy and Chronic PPI Use May Decrease Risk of Colonic Adenomatous Polyps in Helicobacter pylori Infection

Aim. The aim of the paper is to determine association between H. pylori and colonic adenomatous polyps and to explore whether treatment or chronic PPI use can mitigate this risk. Methods. This case-control study included 943 patients who had H. pylori testing and underwent colonoscopy. Presence of polyps was the outcome of interest, whereas age, sex, race, H. pylori infection, triple therapy, and chronic PPI use were independent variables. Multivariate regression analysis was used to calculate odds ratios at 95% confidence intervals. This study was approved by the New York Medical College Institutional Review Board. Results. H. pylori was associated with increased odds of colonic adenomatous polyps (adjusted OR 1.43, 95% CI 1.04–1.77), with stronger association among patients older than 50 (OR 1.65, 95% CI 1.18–2.33). Triple therapy (OR 0.69, 95% CI 0.44–1.07) or chronic PPI use (OR 0.69, 95% CI 0.43–1.09) decreased odds of polyp formation. Analysis revealed a statistically significant reduction in patients who received both triple therapy and chronic PPI, lowering the odds by 60% (adjusted OR 0.43, 95% CI 0.27–0.67). Conclusion. There is increased risk of colonic adenomatous polyps among H. pylori-infected patients. Triple therapy or chronic PPI use may mitigate this risk, with further reduction when these two interventions are combined.


Introduction
Helicobacter pylori (H. pylori) is a bacterium which is indigenous to humans and it is estimated that at least half of the world's population is infected with it [1]. It is well adapted to exist in the stomach throughout the lifetime of its host and to incite a chronic inflammatory state during this period. In the United States, African Americans and Hispanics have been found to have high predilection to this infection compared to Caucasians. Males are equally affected as females [2]. It has been recognized by the International Agency for Research on Cancer as a class I human carcinogen due to its ability to induce gastric adenocarcinoma. It is firmly established that it can also cause extragastric disease, as the bacteria has already been identified in the hepatobiliary system, in the intestines and in feces [3]. Previous investigations linking H. pylori to extragastric cancer have reported finding Helicobacter DNA in 52.6% of hepatobiliary cancer cases [4], prompting investigators to explore the hypothesis that H. pylori may also be associated with intestinal polypoid structures and/or colorectal carcinoma. The pathophysiology was thought to be direct or local carcinogenic effect on colonic epithelia by the bacteria or through stimulation of hypergastrinemia. The presence of H. pylori has been linked with a prolonged and excessive release of gastrin [5], a hormone shown to promote the growth of colon cancer cells in culture [4] and to exert a remote trophic effect on colonic mucosa [4].
Colorectal cancer is the second leading cause of cancerrelated deaths in the United States when both sexes are combined. The American Cancer Society estimates it to cause about 49,700 deaths during 2015 [6].
Prior studies done to determine the association between H. pylori and colonic neoplasia have shown conflicting results. While a number of studies have shown direct correlation between H. pylori carriage and colorectal cancer risk [1,4,[7][8][9][10][11], others failed to show this correlation [3,5,[12][13][14][15]. In this study, we investigated the potential relationship between H. pylori infection and the risk of developing colonic neoplasia. Furthermore, we aimed at specifically exploring how H. pylori treatment with triple therapy and chronic proton pump inhibitor (PPI) use can influence the development or regression of colonic adenomatous polyps.

Study
Population. This is a single-center retrospective case-control analysis of the risk of developing colonic adenomatous polyps among adults with H. pylori infection. Review of electronic medical records of Metropolitan Hospital Center in New York was done during the period from January 1, 2010, to December 31, 2012. Inclusion criteria included adult patients who underwent screening colonoscopy and had an esophagogastroduodenoscopy (EGD) or antigen detection for H. pylori prior to the colonoscopy. We excluded patients who (a) had proven colorectal carcinoma, (b) had high risk of developing colorectal carcinoma (i.e., diagnosed cases of inflammatory bowel syndrome, positive family history of polypoid syndromes, and prior history of carcinoma), and (c) underwent incomplete colonoscopy or had inadequate preparation for colonoscopy. In subjects who underwent multiple EGDs and colonoscopies, we included the index colonoscopy in the analysis. After implementation of our exclusion criteria, we included 943 patients in the final analysis.

Colonoscopy and Definition of Outcomes.
Excised polyps were sent to the Department of Pathology for cytopathologic identification. Colonoscopy result was recorded as being adenomatous polyp positive, hyperplastic polyp, or no polyp. Cases were defined as the presence of biopsy-proven adenomatous polyps, whereas controls were defined as the absence of polyps or presence of hyperplastic polyps. Adenomatous polyps include tubular, tubulovillous, or villous polyps. Data regarding polyp location and number were also obtained. We categorized location as either right-sided for polyps located in the cecum and the proximal two-thirds of the transverse colon, left-sided for polyps located in the distal third of the transverse colon until the rectum, or both for multiple polyps located in both left and right sides.

H. Pylori Status as Exposure.
Exposure was defined as the presence of H. pylori infection prior to colonoscopy. Determination of H. pylori status was made either by the rapid urease test or culture of tissue sample obtained through EGD or by H. pylori antigen detection in serum or stool samples. Data regarding H. pylori treatment with triple therapy and chronic PPI use were gathered. Completion of the course of the triple therapy (two weeks of Amoxicillin and Clarithromycin and six weeks of PPI) was the working definition of treatment in our data collection. Of note, no patients received quadruple therapy in our sample and there were only five patients who received salvage treatment for H. pylori. Chronic PPI use, a variable independent of the H. pylori treatment, was defined as use of any PPI for at least six months prior to or up to the time of the index colonoscopy. Data on use of H 2 blockers, sucralfate, or aluminum-magnesium hydroxide were not gathered nor included in the analysis.

Statistical Analysis.
Baseline characteristics were compared using Chi-square statistics for all categorical variables with more than five. Continuous variables were assessed using Wilcoxon Rank-sum or -test statistics. A two-sided value < 0.05 was considered significant and included in the multivariate regression analysis to determine the risk factors associated with the development of adenomatous polyps. We performed a post hoc analysis wherein we tested for interaction between H. pylori treatment and chronic PPI use in reducing risk for adenomatous polyps in H. pylori-infected subjects.

Cohort Characteristics.
There were 943 patients included in the study. The mean age of the cohort was 57 years with 66% of Hispanic origin. Fifty-nine percent of the patients were females. All patients had complete colonoscopies. Sixtyseven percent had chronic PPI use. H. pylori was detected in 52% ( = 490) of the cohort; and, of these, more than half ( = 282) received treatment. Colonic adenomatous polyps were detected in 23% ( = 216) of the patients.
Patients who developed adenomatous polyps tend to be older (63 versus 56 years) and male (53%). The incidence of H. pylori infection was higher (59% versus 50%) among patients who had adenomatous polyps and there were less chronic PPI users (61% versus 69%) among them. Table 1 shows the baseline characteristics of patients who developed or did not develop colonic adenomatous polyps.

Risk Factors for Colonic Adenomatous Polyps.
In the multivariate regression analysis (Table 3), the risk for developing colonic adenomatous polyps was increased in patients older than 50 years of age (adjusted OR 2.86, 95% CI 1.88-4.35) and those infected with H. pylori (adjusted OR 1.55, 95% CI 1.13-2.12). Males were almost twice likely to develop adenomatous polyps than females (adjusted OR 1.97, 95% CI 1.44-2.69). In contrast, chronic PPI use decreased the odds of adenomatous polyp formation (adjusted OR 0.75, 95% CI 0.54-1.05), although this association was not significant. Table 2 describes the results of the regression analysis in regards to risk factors in the development of adenomatous polyps.
When the cohort was subdivided by age, the odds for colonic adenomatous polyps in H. pylori infection were greater in patients who are older than 50 years of age. A cut-off of 50 years was chosen as this is the recommended age to perform screening colonoscopy. The odds for H. pylori infection among patients below 50 years of age were    above 50 years and being male were also noted to significantly increase the odds of adenomatous polyp development (adjusted OR 2.76 and 1.79, respectively). Triple therapy decreased the risk by almost two-thirds (adjusted OR 0.69, 95% CI 0.44-1.07). The risk was also reduced in patients with chronic PPI use (adjusted OR 0.69, 95% CI 0.43-1.09). In patients who received triple therapy and were also on chronic PPI use, the risk decreased to one-fourth compared to those who were never treated, not on chronic PPI use, or both (adjusted OR 0.26, 95% CI 0.10-0.646). Figure 1 shows the summary of the rates of adenomatous polyps in different sample sets in our study: (1) entire cohort ( = 943), (2) among chronic PPI users ( = 630), (3) among H. pylori-infected patients ( = 490), (4) among H. pyloriinfected patients who received triple therapy ( = 282), and (5) among H. pylori-infected patients who received both triple therapy and were on chronic PPI use ( = 236). The rate of adenomatous polyps was highest among H. pylori-infected patients (26%) but it went down to 21% in those who received triple therapy and to 16% in those who received triple therapy and were on chronic PPI use.

Discussion
The purpose of this retrospective case-control study was to answer three questions. The authors want to determine if the presence of H. pylori infection correlates with an increased likelihood of colonic adenomatous polyp formation. If the answer to this query was affirmative, the next step was to investigate whether receiving triple therapy ameliorated the risk. Lastly we also wanted to ascertain whether chronic PPI use had an influence on the incidence of adenomatous polyp formation.
Our study had four significant findings: (1) H. pylori infection was significantly associated with increased risk of colonic adenomatous polyps, especially in patients older than 50 years of age.
(2) Among noninfected patients, chronic PPI use does not reduce the risk of colonic adenomatous polyp formation.
(3) Triple therapy or chronic PPI use alone does not significantly ameliorate the risk for colonic adenomatous polyps.
(4) The combination of triple therapy and chronic PPI use significantly reduces that risk for colonic adenomatous polyp formation.
In the study that involved the biggest cohort of 156,000 endoscopy results, Sonnenberg and Genta found that H. pylori gastritis increased the odds of developing an adenoma by 1.52 times compared to those without H. pylori infection [11]. Their cohort had similar characteristics as ours: mean age of 57.8 and being female-predominant. Similarly, our data revealed an increased incidence of colonic adenomatous polyps in the presence of H. pylori infection (OR 1.55, value 0.022). Many patients with H. pylori infection are also chronic PPI users. Among those not infected with H. pylori, our data did not reveal any statistically significant difference in the risk of polyp formation among chronic PPI users and nonusers (OR 0.92, 95% CI 0.57-1.50). However, when the analysis was limited to only H. pylori-infected patients, there is note of a tendency for reduction in risk for adenomatous polyp development with chronic PPI use (adjusted OR 0.69, 95% CI 0.43-1.09). This 30% risk reduction was not seen in two studies that explored an association between PPI use and colon adenomas [13,14].
The incidence of colonic adenomatous polyp was less in subjects who received triple therapy for H. pylori, supporting the hypothesis of previous studies that H. pylori might have an influence in the development of colonic polyps. With regard to H. pylori and gastric cancers, studies suggest that treatment of the infection reduces the risk of gastric cancer development by 35% [16,17]. Our analysis suggested a 70% reduction in odds of adenomatous polyp development after adjusting for covariates (adjusted OR 0.69, 95% CI 0.44-1.07).
Yet, no study in our review of existing literature has addressed this relationship.
Finally, we determined whether chronic PPI use and H. pylori treatment may have an additive effect in the reduction of risk for development of adenomatous polyps in H. pylori-infected patients. After testing for interaction, the odds for adenomatous polyps among patients who received triple therapy and were on chronic PPI use decreased to 0.26 (95% CI 0.10-0.646) suggesting that prolonged PPI use and antibiotic therapy for H. pylori may reduce the risk of developing colonic adenomatous polyps.
The internal validity of our study may be reduced by the fact that certain covariates were not included in the analysis. H. pylori carcinogenesis in the stomach, for example, may not be explained by infection alone and other factors may be in play [18][19][20][21]. In addition, certain risk factors for adenomatous polyp formation were also not included in the analysis. Obesity and inactive lifestyle are two studied risk factors for adenomatous polyps [22,23]. Due to a significant loss of data regarding the basal metabolic index (BMI) and social history (smoking, alcohol, and diet), we were not able to include these factors in the analysis. In addition, 66% of our study population was Hispanic and generalizability of our results may be limited to this certain population. Despite these limitations, we believe that our study provides meaningful results to the existing literature. To our knowledge, our study has a sample size second only to the study done by Sonnenberg and Genta [11]. Most importantly, we are able to provide insight about the effect of triple therapy, chronic PPI use, and the combination of both in the risk of adenomatous polyp formation.
In conclusion, H. pylori infection correlated with a higher risk of developing colonic adenomatous polyps. H. pyloriinfected subjects in the older age group (age > 50 years) were more likely to have these polyps than the younger infected population. Most importantly, our data suggest that treatment of the infection and chronic PPI use correlate with a decreased risk of adenomatous polyp among infected individuals, with a further lowering of this risk when these two treatments are combined.