In a previous investigation of the relation of Helicobacter pylori infection to various gastric polyps [5], we found that H. pylori infection was closely associated with hyperplastic polyps and that H. pylori was present in 100% of hyperplastic polyps. This relation is supported by two case reports [6, 7] indicating that clearance and eradication of H. pylori led to the disappearance of hyperplastic polyps. We also reported that 15 polyps (8 to 26 mm in diameter) in a patient with hyperplastic polyps had disappeared by 12 months after eradication of H. pylori [8]. However, these observations were made in only a few patients.

We conducted a randomized, controlled trial to see whether hyperplastic polyps would disappear after eradication of H. pylori.

Methods

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Patients

We enrolled 35 patients (19 men and 16 women; age range, 29 to 75 years) with H. pylori infection and hyperplastic polyps of the stomach diagnosed by endoscopic biopsy. These patients were randomly assigned to one of two groups and sequentially numbered. In the treatment group (n = 17), patients received a proton-pump inhibitor (omeprazole or lansoprazole), amoxicillin, and either clarithromycin or ecabet sodium; in the control group [n = 18], patients had endoscopic examination but did not receive treatment. Our criteria for hyperplastic gastric polyps were 1) hyperplasia of the foveolar epithelium on histologic examination and 2) infiltration of inflammatory cells into the stroma in biopsy specimens [9]. Polyps were diagnosed by two blinded pathologists. Two patients who had hyperplastic polyps 2 mm or less in diameter and 1 patient who did not have H. pylori infection were excluded.

Written, informed consent was obtained from each study participant in accordance with the Declaration of Helsinki (1964) and revisions thereof. The protocol was planned according to the guidelines of the H. pylori eradication trial approved by the committee of the Japanese Society of Gastroenterology. If polyps progressed and were accompanied by malignant transformation, the study was stopped and the polyps were removed endoscopically. After our study was completed, treatment for controls and for patients in whom the first attempt at eradication had failed was proposed in the form of endoscopic removal of polyps or eradication of H. pylori. Data entry and data analyses were done by code so that treatment assignments remained concealed. Compliance with treatment was assessed by pill count.

Endoscopy and Assessment of Eradication of Helicobacter pylori

Patients in the treatment group underwent endoscopy 1 to 3, 7 to 9, and 12 to 15 months after the end of treatment. On each occasion, biopsy specimens were taken from the same areas (three from the antrum and three from the body, exclusive of polyps) for culture, rapid urease testing, and histologic examination. Controls underwent endoscopy 12 to 15 months after enrollment.

The H. pylori cultures were done by using a modified Skirrow agar with 10% horse blood and were incubated for 5 to 7 days at 37°C in a microaerobic atmosphere. We identified H. pylori by colony morphology and biochemical tests, such as urease, catalase, and oxidase activity tests. Rapid urease testing was done with the CLO test (Delta West Pty. Ltd., Bentley, Australia), and the result was considered positive if the color changed after 24 hours. Biopsy specimens for histologic examination were immediately placed in 10% neutral buffered formalin, embedded in paraffin wax, stained with hematoxylin and eosin and with Giemsa, and evaluated for the presence of H. pylori. After patients had fasted overnight, the ¹³C-urea breath test was done by using 100 mg of urea per 100 mL of ¹³C-urea solution. The test result was considered negative if the excess delta ¹³CO_2/sup 12 CO₂ after 15 minutes was less than 5 parts per million.

The presence of H. pylori was determined at each endoscopic examination and was defined by positive results on at least two of four tests: culture, urease testing, histologic examination, and urea breath testing. Eradication of H. pylori was confirmed by negative results on all four tests 1 to 3 months after the end of treatment and at each endoscopic examination. Endoscopists were blinded to treatment assignments. The size and number of polyps were measured at each endoscopic examination by using biopsy forceps (FB-25K, Olympus, Tokyo, Japan) placed near the polyp (open size, 6 mm in diameter; closed size, 2 mm in diameter), and the endoscopic film data on the disappearance and regression of polyps were reviewed independently by two blinded endoscopists.

Histologic Examination, Gastrin Levels, and Titer of IgG to Helicobacter pylori

Histologic diagnosis of the biopsied mucosa of the antrum and body was made by two blinded pathologists. The severity of activity, inflammation, atrophy, and metaplasia was graded on a scale from 1 to 4 and expressed by using the histologic index according to the updated Sydney System [10]: 1 = normal, 2 = mild, 3 = moderate, and 4 = marked.

The serum gastrin level for each patient in both study groups was measured under fasting conditions before the start of treatment and 1, 3, and 12 months after the end of treatment by using radioimmunoassay (GASTRIN-RIA KIT II, Dinabot Co. Ltd., Tokyo, Japan [normal range, 37 to 172 pg/mL]). The titer of IgG to H. pylori was measured by using an enzyme immunoassay kit (HEL-pTEST II, AMRAD Operations Pty. Ltd., Victoria, Australia [range indicating negativity, <30 U/mL]) in serum specimens obtained before treatment and 1, 3, and 12 months after the end of treatment. Laboratory analyses were done by code so that treatment assignments remained concealed.

Statistical Analysis

Pretreatment clinical and laboratory data were analyzed by using the unpaired t-test (for age), the Wilcoxon rank-sum test (for number and size of polyps, histologic findings, serum gastrin levels, and titer of IgG to H. pylori), and the Fisher exact test (for sex, coexisting disease, and distribution of polyps). Post-treatment data were analyzed by using the Fisher exact test (for rates of disappearance, regression of polyps, and eradication of H. pylori) and the Wilcoxon rank-sum test (for histologic and laboratory data). P values less than 0.05 were considered statistically significant. All statistical analyses were done by using STATVIEW software (version 4.02, Japanese edition, Nankodo, Inc., Tokyo, Japan).

Results

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The treatment and control groups were similar with respect to number of patients; age; sex; coexisting disease; number, size, and distribution of polyps; histologic findings; serum gastrin levels; and titers of IgG to H. pylori (Table 1). All patients in both groups completed the entire study protocol and had coexisting chronic atrophic gastritis.

During the follow-up period in the control group, no hyperplastic polyps regressed or disappeared (Table 2). Polyps enlarged or increased in number in 3 of the 18 patients. However, no polyps in the control group were accompanied by malignant transformation.

In the treatment group (Table 2), H. pylori was successfully eradicated without serious side effects in 15 of 17 patients (88% [95% CI, 64% to 98%]), and polyps disappeared in 12 of 17 patients (71% [CI, 44% to 89%]). In 12 of the 15 patients (80% [CI, 52% to 95%]) in whom eradication was successful, disappearance of the polyps and histologic confirmation of a reduction of the inflammatory cell infiltration in the gastric mucosa were seen. The polyps had disappeared in these 12 patients by 3 to 15 months (average, 7.1 ± 1.2 months) after the end of treatment. Smaller polyps tended to disappear within a few months. However, in the 2 patients in whom H. pylori was not eradicated, no polyps showed regression at 12 to 15 months after the end of treatment and no diminution of the inflammatory cell infiltration in the gastric mucosa was seen. The rates of disappearance of polyps in the treatment group were significantly higher than those in the control group (P < 0.001). In patients who received eradication therapy, a significant decrease was seen in serum gastrin levels and titers of IgG to H. pylori compared with those in patients who did not receive eradication therapy (P < 0.001 for serum gastrin levels; P < 0.002 for titers of IgG to H. pylori) (Table 2).

Discussion

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In our study, the disappearance of hyperplastic polyps with histologic confirmation of a reduction in the inflammatory cell infiltration in the gastric mucosa was seen in 12 of the 15 patients (80%) in whom eradication of H. pylori was successful. The polyps had disappeared in the 12 patients by 3 to 15 months (average, 7.1 ± 1.2 months) after the end of treatment. However, none of the polyps in any of the controls or in either of the patients in whom H. pylori was not eradicated showed regression. These results strongly suggest that eradication of H. pylori leads to regression and disappearance of hyperplastic gastric polyps.

The patients in both study groups had high serum gastrin levels (251 pg/mL in the treatment group and 299 pg/mL in the control group) at baseline. Bonilla and associates [11] also reported that patients with hyperplastic polyps had high serum gastrin levels. Because gastrin has a trophic effect on the enterochromaffin-like cells of the gastric mucosa [12] and colonic mucosa [13], an elevated plasma gastrin level is of interest in terms of its effects on cell growth. In a previous study [14], patients with gastric ulcer and H. pylori infection had high gastrin levels (206 pg/mL), but they showed neither foveolar hyperplasia nor hyperplastic polyps in the gastric mucosa and their serum gastrin levels decreased after eradication of H. pylori. Therefore, the decrease seen in serum gastrin levels after eradication of H. pylori in our study is not specifically associated with regression of hyperplastic polyps.

In a previous report [5], we proposed that H. pylori promotes inflammation and contributes to the reactive hyperplasia of the gastric mucosa, which leads to the formation of hyperplastic polyps. Yasunaga and coworkers [15] reported that increased production of interleukin-1 ß and hepatocyte growth factor caused by H. pylori infection may contribute to fold thickening of the stomach by stimulating epithelial cell proliferation and foveolar hyperplasia in patients with enlarged fold gastritis. The intense infiltration of inflammatory cells into the mucosa of the antrum and body disappeared, and the appearance of the mucosa was almost normal after eradication of H. pylori in our study (Table 2). It has been suggested that H. pylori promotes inflammation and increased production of interleukin-1 ß and hepatocyte growth factor and also contributes to the reactive hyperplasia of the foveolar epithelium, which leads to the formation of hyperplastic polyps. It may be premature to draw general conclusions from these observations, but a relation clearly seems to exist among H. pylori and hyperplastic polyps and inflammatory cell infiltration.

It has been recommended [16] that large, pedunculated hyperplastic polyps be snared and removed completely for diagnosis. Because all hyperplastic polyps have malignant potential, it is recommended that all gastric polyps 0.5 cm or more in diameter be removed [17]. Although the hyperplastic polyps were not accompanied by malignant transformation on histologic examination in either study group during the 12- to 15-month follow-up period, recent data strongly suggest a close association between H. pylori infection and gastric carcinoma [18, 19]. We therefore recommend that when hyperplastic gastric polyps are detected on endoscopy, serologic as well as pathologic tests be done to detect H. pylori and eradication of H. pylori be attempted before endoscopic removal is performed. In addition, about 1 year after eradication of H. pylori, any hyperplastic polyps that remain should be removed endoscopically because of the potential for development of cancer.

Drs. Kumagai and Tanizawa: Department of Pathology, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.