The American Journal of Gastroenterology

Helicobacter Pylori is a Risk Factor for Colonic

Neoplasms
Amnon Sonnenberg MD, MSc, Robert M Genta MD

Disclosures
Am J Gastroenterol. 2013;108(2):208-215.

Several previous investigations have studied at the relationship between Helicobacter pylori (H.
pylori) and colonic neoplasms. Two meta-analyses of previous publications have suggested that
infection withH. pylori confers a 1.41.6 fold increased risk for colon adenoma or colon cancer.
[1,2]
These previous studies relied on different variables to assess risk factors and the occurrence of
colonic neoplasm. Although the majority of studies used positive serology as a marker for H.
pylori infection, few studies also used the presence of gastritis or other abnormal gastric
histopathology.[3-5] The occurrence of colon neoplasms was assessed by the endoscopic diagnosis of
adenomatous polyps, villous adenoma, adenocarcinoma, or recurrence of adenomatous polyps after
previous polypectomy.[6-9] All studies suffered from relatively small case populations. The largest
studies included <200 patients with adenomatous polyps. Because of the relatively small odds ratio,
a large population is needed to reliably assess the relationship between H. pylori infection and
presence of colonic neoplasms. In the present study, we utilized a large national database of
156,000 patients who had undergone both a colonoscopy and an esophago-gastro-duodenoscopy
(EGD). The database contained information about the histopathology of the colonoscopy, as well as
the EGD, with detailed information about polyp size, number, and location. The hypothesis of the
present study was that H. pylori gastritis would be a risk factor for all types of colonic neoplasms,
and that such risk would also concern the characteristics of the neoplasms with respect to histology,
number, size, and location.
The data from a large national database of patients who underwent both upper and lower
gastrointestinal endoscopy reveals that H. pylori gastritis confers an increased risk for colonic
neoplasm. The risk applies to all types of colonic neoplasms and appears to increase with advancing
stage of the neoplasm from hyperplastic and adenomatous polyps to tubulovillous adenoma,
adenoma with high-grade dysplasia, and adenocarcinoma. Such risk is not limited H. pylori gastritis,
but is found similarly in other types of gastric histopathology, such as gastric intestinal metaplasia,
gastric adenoma, gastric lymphoma, and gastric cancer.
The strengths of the present analysis relate to the use of histopathology data and the overall size of
our study population. This population was several orders of magnitude larger than that of any
previous report.[1,2] Differently from previous studies, we were also able to consider data regarding
size, number, and location of colonic neoplasms. The reliance on pathology data opened up the
possibility to study different types of gastric, as well as colonic histopathology. These data allowed us
to validate and confirm the associations between gastritis and colonic neoplasms in other gastric

histopathology besides H. pylori gastritis. Immunohistochemical (Hp-IHC) stains are currently

considered the most reliable means to detect Helicobacter in gastric biopsy specimens. Both
specificity and sensitivity are close to 95%.[12,13] In our laboratory, immunohistochemical stains are
performed on all gastric biopsy specimens, ensuring the highest possible histopathological detection
rate.[14] They also open up the possibility to differentiate between H. pylori-positive and -negative
chronic active gastritis. H. pylori-negative chronic active gastritis may reflect on "false negative"
reading, that is, H. pylori infection is present, but because of sampling error, antisecretory
medication, or recent antibiotic use bacteria cannot be seen. Other intra-gastric bacteria may also be
capable of inducing active gastritis, although until now efforts to detect them have proven futile. In
addition, there is a type of focal active H. pylori-negative gastritis frequently found in patients with
inflammatory bowel disease.[15,16] About 10% of patients with celiac disease harbor lymphocytic
gastritis.[17-19] However, this is a distinct entity characterized by the infiltration of the gastric epithelium
by CD3+ lymphocytes. It is highly unlikely that any competent pathologist would diagnose
lymphocytic gastritis as "H. pylori-negative gastritis".[20]
The strengths of the study need to be contrasted with several potential limitations. As the analysis
relied on a database of surgical pathology, little additional demographic data were available
concerning socio-economic status or ethnicity. Similarly, no data were available on present or past
use of antisecretory medications, such as proton pump inhibitors or histamine-2 receptor
antagonists. Some patients with undetectable H. pylori may have undergone a previous antibiotic
therapy. A portion of the patients may have undergone other tests for H. pylori, such as rapid urease
test or serological antibodies, but we had access only to histopathological information. As the
diagnosis of atrophic gastritis is highly unreliable in the absence of multiple mapped gastric biopsy
specimens (usually available only in the setting of prospective studies), we refrained from analyzing
atrophy. We did, however, evaluate intestinal metaplasia, a more easily recognizable from of
mucosal atrophy most frequently associated with H. pylori infection.[21,22] No attempts were made to
classify gastric intestinal metaplasia into complete and incomplete type, or types IIII. As the value of
typing intestinal metaplasia for predicting the risk of gastric cancer is still controversial, and other
methods, such as the OLGA staging, are at least as predictive, typing of gastric intestinal metaplasia
remains primarily a research tool with little if any relevance to clinicians. [23-26]
In order to be included into the study, a patient had to undergo colonoscopy as well as EGD. We
may have missed patients with colonoscopy and EGD but without tissue sent for histopathology. As
gastroenterologists are paid for both endoscopic procedures more and according to different CPT
codes, if they take any mucosal biopsy, there is nowadays a strong incentive to biopsy the slightest
abnormality and take biopsies even from normal appearing mucosa during regular endoscopies.

Biopsies are frequently taken from normal appearing mucosa to rule out presence of H. pylori or
microscopic colitis. A frequent selection of upper gastrointestinal endoscopy for work-up of gastroesophageal reflux disease may have biased the study population against the presence of H. pylori,
[27]

whereas a frequent selection of upper gastrointestinal endoscopy for work-up of dyspepsia or

unspecific abdominal pain could have biased the population in favor of more frequent presence of H.
pylori. Many occasions of bidirectional endoscopy occur for work-up of anemia and suspected
gastrointestinal bleeding, although it is not obvious how such selection might have biased the study
population in favor or against the underlying hypothesis.
The physiological mechanisms underlying the association between H. pylori and colonic neoplasms
are not fully clear. In multiple previous publications it has been assumed that that H. pylori infection
of the gastric mucosa leads to increased levels of serum gastrin, which may act as growth promoting
hormone on the colon mucosa.[28,29] In a recent study by Robertson, gastrin levels were not found to
confer an increased risk for formation of recurrent adenomatous polyps after a previous
polypectomy.[9] However, the gastrin-associated risk for recurrent adenoma may be different from the
risks conferred by a long-term elevation of gastrin for polyps detected during a patient's initial
colonoscopy. Other authors have speculated that H. pylori could act on the colon mucosa itself and
affect polyp growth or promote the development of mucosal dysplasia.[30,31] Lastly, H. pylori could act
as a marker for other related risk factors. H. pylori may function as a proxy measure of general
exposure to poor standards of hygiene and other intestinal infections during childhood. One also
needs to emphasize that the present study is limited to a population from a developed country and
that, for example, the prevalence of H. pyloriinfection in India is relatively high whilst that of colonic
cancer is relatively low.
The present study shows a consistent risk between gastric H. pylori infection and the occurrence of
colonic neoplasm. The results of our study confirm the associations observed by previous
investigators. This association is not restricted to H. pylori-positive gastritis but involves other types
of pathology that may have resulted from infection with H. pylori, such as intestinal metaplasia,
gastric cancer, and gastric lymphoma. Interestingly, other gastric pathology likely unrelated to H.
pylori infection, such as H. pylori-negative chronic active gastritis or chronic inactive gastritis,
showed no or only weak associations with colonic neoplasms. Even if the association between H.
pylori and adenoma is relatively weak, its consistency across different types of gastritis and colonic
neoplasm is striking. Before the advances in public hygiene during the past 50100 years led to a
marked decline in the prevalence of H. pyloriinfection, it used to be the most common infection
among human populations.[32] Irrespective of its relatively low risk, in the past the attributable risk
secondary to its high prevalence may have been quite significant.

In conclusion, the present study shows that various forms of gastritis related to H. pylori infection
confer an increased risk for colonic neoplasm. The mechanism underlying this risk association is
presently not fully understood. The decline in H. pylori may have partly contributed to the declining
time trends of colorectal cancer incidence and mortality observed in may western countries