High prevalence of serum immunoglobulin G antibody to Helicobacter pylori and raised serum gastrin and pepsinogen levels in enlarged fold gastritis

Can J Gastroenterol Vol 11 No 5 July/August 1997 433 Y Yasunaga, JJ Bonilla-Palacios, Y Shinomura, S Kanayama, Y Miyazaki, Y Matsuzawa. High prevalence of serum immunoglobulin G antibody to Helicobacter pylori and raised serum gastrin and pepsinogen levels in enlarged fold gastritis. Can J Gastroenterol 1997;11(5):433-436. To clarify the prevalence of Helicobacter pylori infection in enlarged fold gastritis, serum immunoglobulin (Ig) G antibody to H pylori was determined in 19 patients with severely enlarged gastric body folds (the widest fold greater than 10 mm on the radiograph), 55 patients with moderately enlarged folds (6 to 10 mm) and 44 control subjects (5 mm or less). The prevalence of serum IgG antibody to H pylori in the severe (100%) and moderate groups (100%) was significantly higher than that in controls (34.1%) (P<0.01). There were significant differences among the three groups in serum gastrin, pepsinogen I and pepsinogen II levels (severe had the highest levels, followed by moderate and then controls, P<0.001). H pylori colonization in the gastric mucosa was confirmed by culture, urease test or both, and inflammation by hematoxylin and eosin stain in the 25 H pylori seropositive patients who underwent endoscopy and biopsy. Results suggest that H pylori infection is highly prevalent in enlarged fold gastritis. Further studies on enlarged fold gastritis and H pylori infection are needed.

E nlarged gastric folds are a common finding during radio- graphic or endoscopic examination of adults.Enlarged gastric folds may be associated with a variety of diseases, including hypertrophic gastritis, Ménétrier's disease, Zollinger-Ellison syndrome, primary gastrin cell hyperplasia, carcinoma and lymphoma (1,2).It is critical to determine the cause of this fold enlargement, especially to exclude scirrhous carcinoma.Recently it was suggested that Helicobacter pylori gastritis may be a cause of enlarged gastric folds (3)(4)(5)(6)(7)(8).We previously reported that eradication of H pylori improves inflammation of the gastric mucosa and fold width in H pylori-positive patients with enlarged folds; these findings suggest that H pylori infection may cause gastritis accompanied with enlarged folds, ie, 'enlarged fold gastritis' (6).However, the relationship between the degree of fold enlargement and the prevalence of H pylori infection is unknown.Therefore, to clarify the prevalence of H pylori infection in enlarged fold gastritis, serum immunoglobulin (Ig) G antibody to H pylori (9,10) was determined in subjects with and without enlarged gastric folds.We also measured serum gastrin, pepsinogen I (PGI) and pepsinogen II (PGII) levels, which are known to be elevated in patients with H pylori infection and to decrease after eradication of the organism (10)(11)(12)(13)(14).In addition, H pylori colonization and inflammation in the gastric mucosa were confirmed in some of the H pylori seropositive patients.

SUBJECTS AND METHODS
Nineteen patients with severely enlarged gastric body folds (severe group; 14 males and five females, mean±SEM age 46.3±2.2 years, range 31 to 68), 55 patients with moderately enlarged folds (moderate group; 39 males and 16 females, 45.1±1.2 years, range 30 to 67) and 44 control subjects without enlarged folds (control group; 28 males and 16 females, 45.2±1.2 years, range 31 to 62) comprised the study group.Patients in the severe, moderate and control groups were assigned randomly in one year, three months and one month, respectively, from subjects who underwent upper gastrointestinal barium study as part of a mass screening for gastric carcinoma.All subjects showed gastric folds along the greater curvature in the whole body region on the radiographs.Gastric body folds were considered to be enlarged when the widest fold was greater than 5 mm (deemed severely enlarged at more than 10 mm and moderately enlarged at 6 to 10 mm) on the double contrast radiographs taken in the supine position (15,16).The fold width of the control subjects was, at most, 5 mm.Means ± SEM of the widest fold were 11.4±0.2,7.3±0.1 and 3.7±0.1 mm in the severe, moderate and control groups, respectively.Serum creatinine concentrations were within normal limits.Hypoproteinemia (total protein concentration less than 65 g/L) was found in two patients in the severe group (63 and 64 g/L).
All subjects were free from antisecretory drugs during the study and for at least three months before.The study was performed in accordance with the principles of the local ethical committee, and informed consent was obtained from all subjects.
Twenty-five H pylori seropositive subjects (nine in the severe group, 10 in the moderate group and six in the control group) were randomly selected and underwent endoscopic examinations.Endoscopic examinations in the 19 patients in the severe and moderate groups demonstrated enlarged gastric body folds with and without mucosal erythema or erosions.There were no peptic ulcers or carcinomas found.Endoscopic findings in the six H pylori seropositive control subjects were almost normal.Biopsy specimens were taken from the prepylorus and greater curvature of the upper portion of the body.H pylori infection was determined by positive culture (10,19) (Fujisawa Pharmaceutical Co Ltd, Osaka, Japan) and/or urease test (CLOtest; Delta West, Bentley, Australia) (10,20).Mononuclear infiltrates (for degree of chronic inflammation) and polymorphonuclear infiltrates (for activity of inflammation) were graded into four categories (0, none; 1, mild; 2, moderate; and 3, severe) by hematoxylin and eosin stain (16).
All results are expressed as mean ± SEM.Statistical analyses used were one-way ANOVA, Scheffe's multiple comparison, c 2 test for independence, and the one-and two-sample t tests.P<0.05 was considered statistically significant.In 24 of the 25 H pylori seropositive patients who were endoscoped and biopsied, H pylori was positive in the antrum and the body on culture, urease test or both; in one patient in the severe group it was positive only in the body.Histologic examination showed inflammatory infiltrates in both the antrum and the body (Table 2).In the severe group, polymorphonuclear infiltrates in the body were significantly more severe than those in the antrum (P<0.05);mononuclear infiltrates in both the antrum and the body, and polymorphonuclear infiltrates in the body were significantly more extensive than those in the H pylori seropositive control (P<0.05).In the moderate group, mononuclear infiltrates in the antrum were significantly more severe than those in the H pylori seropositive control (P<0.01).

DISCUSSION
The present study showed that serum H pylori IgG was positive at higher percentages in patients with severely (100%) and moderately enlarged gastric body folds (100%) than in controls without enlarged folds (34.1%).The determination of serum H pylori IgG has high sensitivity and specificity for H pylori infection in the gastric mucosa (9,10).Indeed, in this study, all H pylori seropositive subjects who were endoscoped and biopsied had H pylori colonization in the gastric mucosa on culture and/or urease test.These results suggest that H pylori infection is highly prevalent in enlarged fold gastritis.In agreement with our presented results, comparatively high prevalences of H pylori infection in patients with giant fold (fold width greater than 10 mm) were reported by Stolte et al (5) (88.4%) and Avunduk et al (8) (56.3%).
Our study also showed elevations in serum gastrin, PGI and PGII, and a fall in PGI:PGII ratio in patients with enlarged folds.These findings have frequently been reported in patients with H pylori infection and may predict H pylori infection (10)(11)(12)(13)(14).Our results may also support the hypothesis that enlarged folds are associated with H pylori infection.Moreover, serum PGI and PGII levels reportedly are elevated proportional to the degree of gastric mucosa inflammation, especially in patients with H pylori infection.These levels have been suggested to be indexes of severity of H pylori gastritis (12)(13)(14)21).
Our finding that serum PGI and PGII levels were higher in the severe group than in the moderate and control groups may suggest that inflammation caused by H pylori infection in the severe group is more severe than that in the moderate and control groups.Actually, in this study, inflammatory infiltrates in the body mucosa in the severe group were more extensive than those in the two other groups.Consistent with our results were those of Stolte and co-workers (5), who reported H pylori infection and comparatively severe chronic active inflammation of the body in patients with giant fold gastritis.Inflammation of the gastric body mucosa caused by H pylori infection may be associated with enlarged gastric body folds.
Enlarged gastric folds may be associated with various pathological conditions, including inflammation, hyperplasia of foveolae and/or glands, and neoplasia (1,2).Enhanced epithelial cell proliferation and mild hyperplasia of H pylori-infected gastric mucosa have been reported (22)(23)(24).Enlarged gastric folds in this study may be due not only to inflammatory infiltrates and edema, but also to mucosal hyperplasia.Increased serum gastrin concentrations in subjects with enlarged folds may mean that the trophic effect of gastrin on the gastric oxyntic mucosa ( 25) is associated with enlarged folds.Elevated serum PGI and PGII levels may reflect increases in chief cell and mucous neck cell masses (26,27).Further study is needed to clarify histopathology of enlarged gastric body folds in H pylori gastritis.
The present study, together with our previous report that eradication of H pylori improves inflammation of the gastric mucosa and fold width in H pylori-positive patients with enlarged folds (6), suggests that H pylori infection is a main cause of enlarged fold gastritis.Recently it was suggested that H pylori infection is associated with Ménétrier's disease and hypertrophic lymphocytic gastritis (28)(29)(30)(31), both of which cause enlarged gastric folds.Enlarged fold gastritis may resemble Ménétrier's disease if the former is accompanied with hypoproteinemia, which was found in this study in two patients with severely enlarged gastric folds.Hypertrophic lymphocytic gastritis is considered a rare type of enlarged fold gastritis that is accompanied by a marked increase in lymphocytes in the surface epithelium and gastric pits (29)(30)(31).In this study intra-epithelial infiltration of polymorphonuclear cells, rather than lymphocytes, was found in enlarged fold gastritis.We previously suggested that H pylori infection is one of the causes of 'primary' gastrin cell hyperplasia (4), which also is a type of enlarged fold gastritis.Thus, there IgG was positive in all patients with both severely and moderately enlarged gastric body folds, and in 15 of the 44 control subjects without enlarged folds.The prevalence of serum H pylori IgG in the severe (100%) and moder-Can J Gastroenterol Vol 11 No 5 July/August 1997 Yasunaga et al

TABLE 1 Differences in measured variables among the three groups Prevalence of serum IgG antibody to Helicobacter pylori (%)
Can J Gastroenterol Vol 11 No 5 July/August 1997 435 H pylori in enlarged fold gastritis

TABLE 2
P<0.05 versus H pylori seropositive control; † P<0.05 versus antrum; ‡ P<0.01 versus H pylori seropositive control likely are several special forms of enlarged fold gastritis.It remains unknown what causes the differences between enlarged fold gastritis and H pylori gastritis without enlarged folds, and between enlarged fold gastritis with and without additional characteristics.The present report encourages further studies on enlarged fold gastritis and H pylori infection. *