Helicobacter pylori Infection and Chronic Gastric Acid Hyposecretion

Transcription

1 GASTROENTEROLOGY 1997;113:15 24 Helicobacter pylori Infection and Chronic Gastric Acid Hyposecretion EMAD M. EL OMAR,* KARIN OIEN, ADIL EL NUJUMI,* DEREK GILLEN,* ANGELA WIRZ,* STEPHEN DAHILL, CRAIG WILLIAMS, JOY E. S. ARDILL, and KENNETH E. L. MCCOLL* *University Department of Medicine and Therapeutics and Departments of Pathology and Microbiology, Western Infirmary, Glasgow, Scotland; and Queen s University, Belfast, Northern Ireland Background & Aims: We have identified a subgroup of Helicobacter pylori infected subjects with low or absent gastric acid output. The aim of this study was to document the morphological and functional abnormalities in these subjects and to assess the effect of eradicating the infection. Methods: The 16 hypochlorhydric subjects (6 men) had a mean age of 55 years (range, years). They underwent a 14 C-urea breath test, H. pylori serology, fasting gastrin, gastric autoantibod- ies, gastroscopy with antral and body biopsies, and measurement of peak acid output to pentagastrin (PAO PG ). Their histology was compared with that of age- and sex-matched duodenal ulcer and nonulcer dyspepsia patients (16 each). H. pylori infection was eradicated in the hypochlorhydric subjects, and the investigations were repeated 6 months later. Results: Compared with controls, the hypochlorhydric subjects had less dense H. pylori colonization, body-predomi- nant colonization and gastritis, and increased preva- lence of body atrophy and intestinal metaplasia. Median PAO PG before eradication in the hypochlorhydric subjects was 1.1 mmol/h and increased to 12.6 mmol/h after eradication (P õ 0.001), with no signifi- cant change in body atrophy or intestinal metaplasia. Conclusions: In some subjects, chronic H. pylori infec- tion produces a body-predominant gastritis and pro- found suppression of gastric acid secretion that is partially reversible with eradication therapy. O ver the past few years, we have studied acid secretion in a large number of patients and asymptom- atic volunteers with and without Helicobacter pylori infection. Using gastrin-releasing peptide (GRP) as the stimulus, we found that patients with H. pylori positive duodenal ulcer (DU) had a sixfold higher acid output compared with H. pylori negative healthy volunteers and that this exaggerated acid response resolved after eradication of the infection. 1 In the majority of H. pylori positive nonulcer subjects, GRP-stimulated acid secretion was also increased, although to a lesser extent than ob- served in the patients with DU. 1,2 During the course of these studies, we have identified a subgroup of subjects with evidence of H. pylori infection whose basal and GRP-stimulated acid outputs were zero. It thus appears that H. pylori infection may be associated with various disturbances of gastric secretory function ranging from marked increase to marked decrease in acid output. The purpose of the present study was to document in more detail the morphological and functional abnormalities of the subgroup of subjects with H. pylori infection and acid hyposecretion. In addition, we examined the effect of eradicating H. pylori infection on these abnor- malities. Subjects and Methods Subjects Sixteen of 250 patients and asymptomatic volunteers with H. pylori infection examined over 4 years were identified to be achlorhydric to GRP (40 pmolrkg 01 rh 01 ). Their mean age was 55 years (range, 36 79), and 6 were men. Ten of the 16 subjects were initially referred to the gastrointestinal (GI) clinic for investigation of chronic dyspepsia (mean duration, 30 months; range, months), and the remaining 6 were healthy volunteers taking part in research programs. None of the subjects had undergone any tests involving gastric intubation before identification of the achlorhydria. None of the subjects were receiving any regular medication, although 3 with chronic dyspepsia had received short courses of H 2 -recep- tor antagonists more than 6 months previously. Approximately 2 years after identifying the first of this group of hypochlorhydric subjects, we embarked on a prospective study to document their gastric morphology and function in more detail and their response to eradication therapy. Methods Design. All 16 hypochlorhydric subjects had a de- tailed initial assessment including 14 C-urea breath test, mea- surement of H. pylori immunoglobulin (Ig) G and IgM serol- Abbreviations used in this paper: DU, duodenal ulcer; GI, gastroin- testinal; IM, intestinal metaplasia; NUD, nonulcer dyspepsia; PAO PG, peak acid output in response to pentagastrin by the American Gastroenterological Association /97/$3.00

2 16 EL OMAR ET AL. GASTROENTEROLOGY Vol. 113, No. 1 (CLO test; Delta West Pty. Ltd., Bentley, Australia), and the other two biopsy specimens were placed in 10% formalin and submitted for histological examination. Acid secretory studies. Acid secretory studies were performed within 1 week of the endoscopy. After a 12-hour fast, an orogastric tube (Anderson Inc., New York, NY) was swallowed, and its position in the dependent part of the stom- ach was checked using the water-recovery test. 5 Intermittent suction was then applied using an intermittent suction unit (Ohmeda, Columbia, MD) that applies suction for 20 seconds in each 32-second cycle. An intravenous infusion of pentagas- trin (Peptavlon; ICI, Cheshire, England) was started at a rate of 0.6 mgrkg 01 rh 01 to stimulate maximal acid secretion. Gastric juice was collected for 1 hour in 15-minute aliquots. The volume of each 15-minute gastric juice collection was recorded, and its hydrogen ion concentration was measured by titration with 0.1 mol/l NaOH to ph 7 using an autotitrator (Radiometer ETS 822; Copenhagen, Denmark). The acid output per 15-minute period was then calculated by multiplying the volume by the hydrogen ion concentration. Peak acid output in response to pentagastrin (PAO PG ) was calculated by taking the mean of the two highest consecutive 15-minute collections and expressed as millimoles per hour. Histological examination of stomach biopsy speci- mens. Antral and body biopsy specimens were embedded in paraffin, and 4-mm sections were obtained. Sections at three levels were stained with H&E and assessed for the parameters discussed below. One section was stained using cresyl fast violet for assessment of H. pylori colonization. In equivocal cases, immunohistochemistry was used to confirm the presence or absence of H. pylori organisms. The biopsy specimens were scored blindly without knowledge of diagnosis, H. pylori status, or acid output. Five morpho- logical parameters were assessed using the Sydney system 6,7 and graded from 0 to 3 (equating to none, mild, moderate, and severe). The five parameters were as follows: (1) inflammation, which scored the chronic inflammatory infiltrate in the lamina propria; (2) activity, which scored the acute inflammatory in- filtrate chronic and acute inflammatory scores (1 and 2) were added together, giving a total inflammatory score with a possi- ble maximum of 6 (range, 0 6); (3) atrophy, scored from 0 to 3 on the basis of proportion of glandular loss 6,7 ; (4) intestinal metaplasia, scored from 0 to 3 on whether absent or occupying less than one third, more than one third, or more than two thirds of the mucosa present; and (5) H. pylori colonization, scored only when definitely recognized by morphology and special stains and graded from 0 to 3. In this study, we used the Sydney classification of gastritis. 6,7 Previous investigations have shown that this could be applied consistently by histopathologists. 8 Perhaps the most difficult area is the assessment of gastric atrophy; in recent literature, analog scales have been included. 7,9 These were not available at the start of our study, and instead, two pathologists agreed on the grade of atrophy (0 3) of a number of selected gastric biopsy specimens; these were used as comparisons for subse- quent assessment. ogy, parietal cell and intrinsic factor antibodies and fasting gastrin, upper GI endoscopy and biopsies from antrum and body of stomach for histology, and rapid urease slide test. They also had their peak acid output measured in response to stimulation by pentagastrin. These tests are described in detail later. After this initial assessment, 11 of the hypochlorhydric subjects were treated with H. pylori eradication therapy and reexamined 6 months after documented eradication. The other 5 subjects agreed to have their acid secretory studies repeated 1 year after initial assessment without receiving any eradication therapy to exclude the possibility of spontaneous resolution of the hypochlorhydria. After this, they also underwent eradication therapy and were reexamined 6 months after documented eradication. Five subjects also agreed to have a second posttreatment acid secretory study performed 18 months after eradication of the infection. Details of Initial Assessment 14 C-urea breath test. The 14 C-urea breath test was per- formed as previously reported. 3 In our laboratory, the 20-min- ute value (expressed as kilograms percent dose per millimole CO 2 times 100) is used for diagnosis. Values ú40 are regarded as positive and those õ20 as negative. Values between 20 and 40 are regarded as equivocal. H. pylori serology. All subjects had H. pylori IgG and IgM serology measured using the Bio-Rad G.A.P. enzyme- linked immunosorbent assay kit (Bio-Rad Laboratories, Herts, England). Serum samples were incubated at 25 C for 10 min- utes, and absorbance was measured at 450 nm. The results were read from a point standard curve constructed from the OD values obtained from five calibrators. The positive cutoff point for H. pylori IgG was taken as 14 U and for IgM as 50 U. The specificity and sensitivity of the assays were determined in our local population and gave values of 93% and 90%, respectively. Basal gastrin. A fasting blood sample was obtained before endoscopy for gastrin determination, and the plasma was stored at 020 C. Gastrin levels were measured by radioimmunoassay using antiserum R98, which has a sensitivity of 5 ng/l. 4 It binds gastrin 17 and gastrin 34 with equimolar potency. Parietal cell and intrinsic factor antibodies. Parietal cell and intrinsic factor antibodies were measured from serum samples on all the hypochlorhydric subjects. Rat stomach tis- sue was used as the source of parietal cell and intrinsic factor antigens, and positive reactions were measured using an immunofluorescence assay. Upper GI endoscopy and stomach biopsies. Subjects reported at 9 AM after a 12-hour fast. Intravenous sedation was given, and standard upper GI endoscopy was performed to identify any macroscopic abnormalities. Three biopsy speci- mens were obtained from the antral region within 2 cm of the pyloric ring and three from the body region of the stomach between 50 and 55 cm along the greater curvature. A biopsy specimen from each site was used for the rapid urease test

3 July 1997 H. PYLORI AND ACID HYPOSECRETION 17 Figure 1. Combined inflammatory score in (A) antrum and (B) body of stomach in hypochlorhydric subjects (H/C), patients with DU, and patients with NUD. For the purposes of comparison of stomach morphology, hiatus hernias. One had plaques of intestinal metaplasia two groups of controls were chosen. The first consisted of 16 in the antrum (confirmed histologically). After eradicapatients with endoscopically proven DU disease. Their mean tion, the endoscopic findings were unchanged, except for age was 56 years (range, 37 77), and 6 were men. The second the development of esophagitis in 1 patient. group consisted of 16 patients with nonulcer dyspepsia (NUD) who had normal upper GI endoscopy and normal acid secretory Histology of Antral and Body Biopsies function (defined as a peak acid output to pentagastrin stimula- Combined inflammatory score. Before eradication ú22 mmol/h). Their mean age was 54.4 years (range, tion, the median antral inflammatory score was 2 (range, 35 69), 6 were men, and their median PAO PG was 29 mmol/ 1 5) in the hypochlorhydric group compared with 5 h (range, 22 48). All three groups were matched for age, sex, (range, 2 6) in the patients with DU and 5 (range, 2 and body weight. Three antral and three body biopsy specimens were obtained during endoscopy and were treated as 6) in the patients with NUD (P õ for both). The previously described. median body inflammatory score was 4 (range, 1 6) in Eradication of H. pylori. All 16 hypochlorhydric sub- the hypochlorhydric group compared with 2 (range, 1 jects were given H. pylori eradication therapy in the form of 4) in the DU group and 2 (range, 1 4) in the NUD a 2-week course of amoxicillin, 500 mg three times daily, group (P õ for both) (Figure 1). Within the hypo- metronidazole, 400 mg three times daily, and tripotassium chlorhydric group, the body gastritis was significantly dicitratobismuthate, 120 mg three times daily. Six weeks after more marked than the antral gastritis (P õ 0.005). In receiving this treatment, a 14 C-urea breath test was performed contrast, both the patients with DU and and those with to assess success of eradication; if negative, the patients were NUD had a significantly more marked antral gastritis invited back 5 months later to undergo posteradication studies. compared with the body (P õ 0.001). In those who failed to respond to the initial eradication regi- Six months after eradication, the median antral inmen, a 2-week course of clarithromycin, 500 mg three times flammatory score in the hypochlorhydric group decreased daily, amoxycillin, 500 mg three times daily, and metronidato 1 (range, 1 2; P õ 0.01 vs. before eradication). In zole, 400 mg three times daily, was given, and success of treatment was assessed as previously described. the body, the median inflammatory score decreased to 1 Statistical analysis. Statistical analysis for unpaired (range, 1 3; P õ vs. before eradication) (Figure data was performed using the Mann Whitney U test and for 2A). paired data using the Wilcoxon test. Significance was taken at Atrophy. Before eradication, the median antral at- the 5% level. rophy score was 0 (range, 0 3) in the hypochlorhydric The study was approved by the Western Infirmary Ethics group and was similar to that in patients with DU and Committee, and all subjects gave informed written consent. NUD (DU median, 0, and range, 0 1; NUD median, Results 0, and range, 0 1) (P Å 0.47). In contrast, the median Upper GI Endoscopy body atrophy score was 2 (range, 0 3) in the hypochlorhydric group, with 13 of the 16 subjects showing On initial endoscopy, none of the 16 hypochlorhydric varying degrees of atrophy, whereas none of the DU or subjects had ulcers or erosions. Three had small NUD patients showed any body atrophy (Figure 3).

4 18 EL OMAR ET AL. GASTROENTEROLOGY Vol. 113, No. 1 Figure 2. Morphological changes before and 6 months after eradication of H. pylori infection in the antrum and body of hypochlorhydric subjects. (A) Combined inflammatory score, (B) atrophy score, and (C) intestinal metaplasia score. Six months after eradication, there was no statistically and NUD patients did not achieve statistical significance, significant change in the degree of antral or body atrophy although there was a strong trend (P Å 0.056; Figure in the hypochlorhydric group, although there was a trend 4). toward improvement in the body atrophy (P Å 0.08) Six months after eradication, there was no overall (Figure 2B). change in the degree of antral or body IM in the hypochlorhydric Intestinal metaplasia. Before eradication, the subjects. In the body, 2 subjects showed a median antral intestinal metaplasia (IM) score was 0 2-point improvement, 2 subjects showed a 1-point improvement, (range, 0 3) in the hypochlorhydric group and was similar 2 subjects showed a 1-point deterioration, to that in patients with DU and NUD (DU median, and the rest were unchanged (Figure 2C). 0, and range, 0 1; NUD median, 0, and range, 0 2) H. pylori density. The median antral H. pylori (P Å 0.68). In the body, the median IM score was 0 density score in the hypochlorhydric group was 0 (range, (range, 0 3) in the hypochlorhydric group, although 7 0 3). Their median body H. pylori density score was 1.5 of 16 subjects showed varying degrees of IM (5 were (range, 0 3). Indeed, in 9 of 16 subjects, H. pylori could complete and 2 were incomplete). None of the patients not be confidently identified in the antrum. Of these 9 with DU or NUD showed any IM in the body. The subjects, 4 had H. pylori organisms confidently identified difference between the hypochlorhydric subjects and DU in the body, leaving 5 subjects in whom H. pylori could Figure 3. Gastric atrophy score in (A) antrum and (B) body of stomach in hypochlorhydric subjects (H/C), patients with DU, and patients with NUD.

5 July 1997 H. PYLORI AND ACID HYPOSECRETION 19 Figure 4. Intestinal metaplasia score in (A) antrum and (B) body of stomach in hypochlorhydric subjects (H/C), patients with DU, and patients with NUD. not be identified in either antral or body biopsy speci- Acid Secretion mens using histology. In patients with DU and those Before eradication, 5 hypochlorhydric subjects unwith NUD, H. pylori was identified readily in all patients derwent repeat pentagastrin-stimulated acid secretory with median scores of 3 (range, 2 3) and 2 (range, 1 studies separated by a period of 6 months to 2 years. 3) for antrum and body, respectively (Figure 5) (P õ PAOPG s on the first occasion were 0, 0, 1, 6, and for DU and NUD vs. hypochlorhydrics in the mmol/h and on the second occasion were 0, 0, 1.1, 6.8, antrum; P Å NS for DU and NUD vs. hypochlorhydrics and 7.8 mmol/h, respectively. in the body). The median PAO PG in the 16 hypochlorhydric sub- Six months after eradication, H. pylori was not detected jects before eradication was 1.1 mmol/h (range, 0 7.8). in any of the biopsy specimens from the hypochlorhydric Fifteen of these were reexamined 3 6 months after eradigroup. cation. Their PAO PG increased from a median of 1.1 Ratio of H. pylori colonization density to inflam- (range, 0 7.8) before eradication to a median of 12.6 mation in body mucosa. The ratio of H. pylori coloniza- mmol/h (range, ) after eradication (P õ 0.001; tion density to body inflammation score in the hypo- Figure 7). chlorhydric subjects was 0.33 (range, 0 2) and was In the 5 subjects who agreed to be examined at both significantly lower than in patients with DU (median, 6 and 18 months after eradication, 1 showed a further 1; range, 0.5 2) and those with NUD (median, 1; range, increase in PAO PG from mmol/h, 1 decreased from ) (P õ 0.01; Figure 6) mmol/h, and the other 3 showed no further Figure 5. H. pylori colonization density in (A) antrum and (B) body of stomach in hypochlorhydric subjects (H/C), patients with DU, and patients with NUD.

6 20 EL OMAR ET AL. GASTROENTEROLOGY Vol. 113, No. 1 Figure 6. Ratio of H. pylori colonization density to body inflammation in hypochlorhydric subjects (H/C), patients with DU, and patients with NUD. Figure 8. Basal gastrin concentrations (nanograms per liter) before and 6 months after eradication of H. pylor infection in hypochlorhydric subjects. However, there was no correlation with the presence of hiatus hernia. Basal Gastrin recovery in PAO PG (6 months after: 2.4, 12.6, and 7.5 mmol/h; 18 months after: 3.5, 11.9, and 6.9 mmol/h, respectively). Interestingly, 6 of the 15 subjects have spontaneously complained of developing heartburn after eradication of the infection and restoration of acid secretion, and 1 subject was found to have grade I esophagitis. The symp- toms of heartburn occurred in patients who had a greater improvement in their PAO PG after eradication. The me- dian increase in PAO PG in those who developed heartburn after eradication was 12.6 mmol/h (range, ) compared with a median of 7.5 mmol/h (range, ) in those who did not complain of heartburn (P õ 0.03). The median basal gastrin concentration in the hypochlorhydric group before eradication was 40 ng/l (range, 5 300). This was not statistically different from basal gastrin levels obtained from previous studies from infected healthy volunteers (median, 45; range, 10 90), infected NUD patients (median, 60; range, ), and infected DU patients (median, 60; range, ). 2 After eradication, the median basal gastrin concentration in the hypochlorhydric group decreased to 20 ng/l (P õ 0.05; Figure 8). Parietal Cell and Intrinsic Factor Antibodies Fourteen of the 16 subjects had negative parietal cell and intrinsic factor antibodies. Two subjects had weakly positive parietal cell antibodies. None of the subjects had positive intrinsic factor antibodies. Figure 7. PAO PG (millimoles per hour) before and 6 months after eradication of H. pylori infection in hypochlorhydric subjects. H. pylori Serology The median H. pylori IgG titer in the hypochlorhydric group was 30.3 U (range, ) and was similar to that in patients with DU and NUD (median, 24.4; range, 9 68) (P Å 0.70). Using the cutoff titer of 14 U to indicate seropositivity, 2 of the hypochlorhydric subjects and 1 of the DU patients were seronegative. All 3 seronegative subjects had positive 14 C-urea breath test results. H. pylori IgM titers were negative in all subjects studied.

7 July 1997 H. PYLORI AND ACID HYPOSECRETION 21 Table 1. Summary of H. pylori Confirmatory Tests produced no acid at all, i.e., total achlorhydria. The achlorhydria did not appear to be autoimmune in origin Antral Body Antral Body IgG No. C UBT CLO CLO histology histology serology because none of the subjects had antibodies to intrinsic factor. Despite being profoundly hypochlorhydric, the 1 / / / / / / 2 / / / / / / majority did not have marked hypergastrinemia, and in 3 / / / / / / this respect, were again distinct from autoimmune 4 / / / / / / achlorhydria, which is typically accompanied by pro- 5 / / / / / / 6 / / / / / / foundly elevated gastrin levels / / / / / / Morphologically, the hypochlorhydric subjects were 8 / / / 0 / / characterized by gastritis, which predominantly involved 9 / / / 0 / / 10 / / / 0 / / the body of the stomach. In addition to the inflammation, 11 / / / 0 0 / 13 of 16 hypochlorhydric subjects also had varying de- 12 / 0 / 0 / / grees of atrophy, and 7 had intestinal metaplasia in the 13 / / / Equivocal / body region. The pattern of gastritis in the hypochlorhy- 15 Equivocal / dric subjects was different from that in patients with DU 16 / and NUD positive for H. pylori with normal acid secretion CLO, rapid urease slide test; UBT, urea breath test. whose gastritis was more marked in the antrum than in the body. In addition, patients with DU and NUD were characterized by absence of body atrophy and intes- H. pylori Urease Tests tinal metaplasia. 14 C-urea breath test. Fourteen of 16 subjects had Evidence of current H. pylori infection was found in positive 14 C-urea breath test results. The remaining 2 each of the hypochlorhydric patients. However, detection subjects had breath test results that were in the equivocal of the infection was more difficult than in the patients range (i.e., kg% dose/mmol CO ). with DU or NUD, and several of the patients would Rapid urease slide test. Twelve of 16 subjects have been classified as H. pylori negative if only one or had positive antral rapid urease slide test results, and 13 two H. pylori diagnostic tests had been used. Indeed, had positive body rapid urease slide test results. Three subjects only had one unequivocally positive test subjects had negative rapid urease slide test results from and might be classified as negative by some investigators. both sites, and 1 subject had a negative antral rapid However, the two positive tests criterion for diagnos- urease slide test result and a positive body rapid urease ing H. pylori infection may be inappropriate for subjects slide test result. with achlorhydria because it is recognized that the den- Table 1 summarizes the results of the H. pylori tests sity of H. pylori colonization is reduced in the absence of on the 16 hypochlorhydric subjects. gastric acid Eradication therapy led to a significant Discussion improvement in antral and body gastritis in all subjects, including the 3 with only one positive test. This is consistent The present study investigated gastric mucosal with them having sparse colonization with H. pylori, morphology and function in a subgroup of subjects with which is difficult to demonstrate by conventional means chronic nonautoimmune gastric hypochlorhydria and asand and yet still able to exert effects on gastric morphology sessed the role of H. pylori infection in the disorder. Our function. findings indicate that the condition is predominantly In the hypochlorhydric subjects, H. pylori like organ- caused by H. pylori and that eradication of the infection isms were more abundant in the body than antral mucosa, results in variable degrees of restoration of gastric secrein which contrasts with the patients with DU and NUD tory function. whom the density of colonization with H. pylori tended Although initially detected by achlorhydria in repattern to be greater in the antrum than body. This differing sponse to GRP, the subjects studied were subsequently of distribution may also be secondary to gastric confirmed to be achlorhydric or profoundly hypochlorhyacid acid status because it has been shown that inhibition of dric in response to a supraphysiological dose of pentagasbution secretion in patients with DU changes their distri- trin. PAO PG is a more sensitive measure of acid hyposepredominance. of H. pylori from antral predominance to body cretion than GRP-stimulated acid output because it 15 It seems that the oxyntic mucosa of DU assesses the maximal acid-secreting capacity of the oxynhospitable patients with its characteristic high acid secretion is less tic mucosa. 10 The highest PAO PG in the group was 7.8 to H. pylori colonization than that of patients mmol/h (normal, ú15 mmol/h), and 7 of 16 subjects with low acid secretion.

8 22 EL OMAR ET AL. GASTROENTEROLOGY Vol. 113, No. 1 A further morphological difference between the hypo- necessary for esophagitis. This observation may be relevant chlorhydric subjects and patients with DU was the degree to the symptomatic response to H. pylori eradication of body gastritis relative to density of H. pylori coloniza- therapy in subjects with NUD. tion. The acid hyposecretors had slightly less dense H. The early recovery in gastric acid secretion coincided pylori colonization of the body mucosa than the patients with eradication of the infection and resolution of the with DU, yet had much more severe inflammation of the inflammation of the oxyntic mucosa. This is consistent body mucosa. This more marked inflammatory response with the H. pylori related body gastritis impairing the by the body mucosa to H. pylori may be a consequence acid secretory function of the oxyntic mucosa. A recent of low acid secretion. Recent studies have shown that study by Feldman et al. 18 has shown a positive correlation inhibition of acid secretion by proton pump inhibitors between the severity of H. pylori related body gastritis results in a marked increase in the severity of body gastri- and the degree of reduction in acid secretory function. tis relative to H. pylori density in DU subjects. 16 It thus The mechanism(s) by which H. pylori associated inappears that active acid secretion may somehow protect flammation of the body of the stomach inhibits gastric the oxyntic mucosa from H. pylori induced gastritis. acid secretion is unclear. However, the infection stimu- This may be related to a local ph effect or simply the lates production of interleukin 1b by the gastric muhigh volume of secretion washing away bacterial toxins. cosa, 19 and this cytokine is a powerful inhibitor of acid In summary, there were four morphological differences secretion. 20 between the hypochlorhydric subjects and patients with This subgroup of hypochlorhydric patients demon- DU and NUD who had normal acid secretion: (1) less strates the complex two-way interaction between H. pydense colonization in hypochlorhydric subjects, (2) body- lori gastritis and gastric acid secretory function. The H. predominant colonization and gastritis in hypochlorhy- pylori body gastritis is inhibiting acid secretion and the dric subjects, (3) increased inflammation relative to H. low acid secretion is modifying H. pylori gastritis as prepylori density in the body of hypochlorhydric subjects, viously detailed. and (4) increased prevalence of atrophy and intestinal The degree of recovery of acid secretion was variable, metaplasia in body mucosa of hypochlorhydric subjects. with some regaining normal or near-normal values while The role of H. pylori infection in the morphological and others remained significantly hypochlorhydric even 18 functional abnormalities in the hypochlorhydric subjects months after eradication. The persisting hypochlorhydria was investigated by assessing the response to eradication in these patients is consistent with lack of resolution of of the infection. In the subjects with acid hyposecretion, the atrophy and intestinal metaplasia. It thus appears that eradication of H. pylori infection resulted in resolution the inflammation and associated functional inhibition of of the gastritis, with only a mild degree of inflammation acid secretion are both readily reversed by eradication of remaining 6 months after treatment. This is in agreement H. pylori infection. In contrast, the atrophy and impairwith previous studies that have shown mild persisting ment of acid secretion associated with that are not readily inflammation 6 18 months after eradication of H. pylori reversed by eradicating H. pylori. These findings are in infection. 17 In contrast to the improvement in inflamma- keeping with the work by Ruiz et al. 21 who studied a tion, gastric atrophy and intestinal metaplasia did not population with a high prevalence of multifocal atrophic improve significantly, although some subjects showed a gastritis. They found that advanced atrophy was associdegree of recovery. Our subjects have so far been followed ated with high fasting gastric ph that decreased after up for 6 months, which may be too short to demonstrate eradication of the infection. This improvement in acid reversibility of the atrophy and intestinal metaplasia. secretion coincided with improvement in the inflammation There was a highly significant recovery in gastric acid and persistence of the atrophy. secretion within 6 months of eradication of the infection. There is some evidence that acute H. pylori infection However, this was variable and ranged from minimal may cause hypochlorhydria This usually resolves increase to restoration of normal levels of acid secretion. within a few months, although the study by Ramsey et The repeat acid studies 18 months later indicated that al. 24 suggested that in some subjects, the hypochlorhydria after the initial recovery of acid secretion there was little may become chronic. The subjects reported in our present or no further increase with the passage of time. study appeared to have hypochlorhydria associated with Interestingly, 6 subjects developed new onset of heartburn chronic H. pylori infection. The evidence for this includes coincident with return of acid secretion, and 1 had the following. First, 5 of our subjects had repeat acid new endoscopic evidence of esophagitis. It therefore secretory studies before institution of H. pylori eradication seems that in some patients, eradication of H. pylori can therapy and showed no spontaneous recovery of acid secretion induce dyspepsia by restoring levels of acid secretion after 1 year. Second, the presence of gastric atro-

9 July 1997 H. PYLORI AND ACID HYPOSECRETION 23 phy in 13 of 16 subjects and intestinal metaplasia in 7 those observed in patients presenting with gastric cancer. of 16 subjects suggests that the infection has been present for a number of years; it is unlikely that these changes It is therefore likely that the subgroup of patients who would develop in the context of an acute infection. Third, develop chronic acid hyposecretion is likely to have an the mean age of our subjects was 55 years, and acquisition increased risk of gastric cancer and account for the associof the infection at this age is thought to be rare. Fourth, ation between the infection and gastric carcinoma. Our the negative IgM serology and positive IgG serology finding that the functional and morphological abnormalexclude acute infection because H. pylori IgG seroconver- ities are partly reversible supports the concept that eradision takes at least 3 months to occur. 28,29 cation of H. pylori infection may reduce the chance of We have previously reported that H. pylori infection subsequently developing gastric cancer. However, our in patients with DU is associated with acid hypersecrecretion study also indicates that the degree to which the hypose- tion that resolves after eradication of the infection. 1 We can be reversed is variable and that, in some have now confirmed that in some subjects, the infection patients, an irreversible stage is reached. The major chalinduces hyposecretion of acid, which is also partially reversible lenge is to be able to identify this subgroup before irre- versed in some, but not in others, by eradication of the damage occurs. infection. There are several possible explanations for these different outcomes of H. pylori infection. Differences in References bacterial strains may be important. The main bacterial 1. El-Omar E, Penman I, Ardill JES, Chittajallu RS, Howie C, McColl characteristic currently associated with clinical disease KEL. Helicobacter pylor infection and abnormalities of acid secre- tion in patients with duodenal ulcer disease. Gastroenterology is cytotoxin-associated gene A. However, this is more 1995;109: common in both patients with DU 30 and subjects with 2. El-Omar E, Penman I, Ardill JES, McColl KEL. A substantial proportion atrophy and intestinal metaplasia 31 and therefore does of NUD patients have the same abnormality of acid secretion as DU patients. Gut 1995;36: not explain the divergence of outcome. Differences in 3. Neithercut WD, Milne A, Chittajallu RS, El-Nujumi AM, McColl the host s premorbid acid secretory status may be im- KEL. Detection of Helicobacter pylori infection by measurement portant. In subjects with premorbid high acid secretion, of gastric aspirate ammonium and urea concentrations. Gut the infection will predominantly colonize the antrum, 1991;32: Mullholand G, Ardill JES, Fillmore D, Chittajallu RS, Fullarton GM, and the H. pylori induced hypergastrinemia will further McColl KEL. Helicobacter pylori-related hypergastrinaemia is due increase the acid, thus predisposing to DU disease. How- to a selective increase in gastrin G17. Gut 1993;34: ever, in subjects with premorbid low acid secretion, the 5. Hassan HA, Hobsley H. Positioning of subject and of nasogastric tube during a gastric secretion study. BMJ 1970;1: infection will be able to colonize the body mucosa and 6. Price AB. The Sydney system: histological division. J Gastroentinduce a body gastritis that will further compromise the erol Hepatol 1991;6: acid-secreting capacity of the oxyntic mucosa. Other gegrading 7. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and netic factors such as epithelial expression of blood group of gastritis: the updated Sydney system. Am J Surg Pathol 1996;20: antigens and secretor status may affect the distribution 8. Andrew A, Wyatt JI, Dixon MF. Observer variation in the assessof the infection on the gastric mucosa and subsequent ment of chronic gastritis according to the Sydney system. Histopathology effect on acid secretory function. Dietary factors such as 1994;25: Genta RM. Recognizing atrophy: another step toward a classifisalt and vitamin C intake may also modify the gastritis cation of gastritis. Am J Surg Pathol 1996;20(Suppl 1):S23 and associated acid secretory function. S30. This subgroup of subjects with H. pylori induced 10. McColl KEL, El-Omar E. Gastrin releasing peptide and its value chronic acid hyposecretion is likely to be relevant to in assessing gastric secretory function. Aliment Pharmacol Ther 1995;9: the recognized association between H. pylori and gastric 11. Banerjee S, Ardill JES, Beattie AD, McColl KEL. Effect of omepracancer. The patients examined in this study show a con- zole and feeding on plasma gastrin in patients with achlorhydria. siderable number of functional and morphological fea- Aliment Pharmacol Ther 1995;9: Logan RPH, Walker MM, Misiewicz JJ, Gummett PA, Karim QN, tures associated with the subsequent development of gas- Baron JH. Changes in the intragastric distribution of Helicobacter tric cancer. Chronic gastric acid hyposecretion or pylori during treatment with omeprazole. Gut 1995;36: complete achlorhydria is a well recognized and important 13. Faisal MA, Russell RM, Samloff IM, Holt PR. Helicobacter pylori infection and atrophic gastritis in the elderly. Gastroenterology risk factor for gastric cancer. 32 Our patients also showed 1990;99: little increase in gastrin despite their hypochlorhydria, 14. Fong T-L, Dooley CP, Dehesa M, Cohen H, Carmel R, Fitzgibbons and this combination has been reported in patients with PL, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection in pernicious anemia: a prospective controlled study. Gastroenterolearly gastric cancer. 33 The morphological characteristics ogy 1991;100: of our hyposecretors, i.e., body-predominant gastritis, 15. Kuipers EJ, Uyterlinde AM, Pena AS, Hazenberg HJA, Bloemena atrophy, and intestinal metaplasia, are also typical of E, Lindeman J, Klinkenberg-Knol EC, Meuwissen SGM. Increase

10 24 EL OMAR ET AL. GASTROENTEROLOGY Vol. 113, No. 1 of Helicobacter pylori-associated corpus gastritis during acid sup- Campylobacter pylori gastritis. Am J Gastroenterol 1988;83: pressive therapy: implications for long-term safety. Am J Gastroenterol ;90: Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rath- 16. Solcia E, Villani L, Fiocca R, Luinetti O, Boldorini R, Trespi E, bone BJ, Heatley RV, Axon ATR. Acute Helicobacter pylori infec- Perego M, Alvisi C, Lazzaroni M, Bianchi Porro G. Effects of eraditric tion: clinical features, local and systemic immune response, gascation of Helicobacter pylori on gastritis in duodenal ulcer paconcentrations. mucosal histology, and gastric juice ascorbic acid tients. Scand J Gastroenterol 1994;29(Suppl 201): Gut 1991;32: Rauws EA, Langenberg W, Houthoff HJ, Zanen HC, Tytgat GN. 30. Blaser MJ. Intrastrain differences in Helicobacter pylori: a key Campylobacter pyloridis-associated chronic active antral gastri- question in mucosal damage? Ann Med 1995;27: tis. a prospective study of its prevalence and the effects of antibacter 31. Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ. Helicobacterial and antiulcer treatment. Gastroenterology 1988;94: pylori and atrophic gastritis: importance of the caga sta tus. J Natl Cancer Inst 1995;87: Feldman M, Cryer B, McArthur CE, Huet BA, Lee E. Effects of 32. Hastrup Svendsen J, Dahl C, Bo Svendsen L, Christiansen PM. aging and gastritis on gastric acid and pepsin secretion in huup Gastric cancer risk in achlorhydric patients: a long-term follow- mans: a prospective study. Gastroenterology 1996;110:1043 study. Scand J Gastroenterol 1986;21: Haruma K, Yoshihara M, Sumii K, Tari A, Watanabe C, Kodoi A, 19. Yamaoka Y, Kita M, Kodama T, Sawai N, Imanishi J. Helicobacter Kajiyama G. Gastric acid secretion, serum pepsinogen I, and pylori caga gene expression of cytokine messenger RNA in gastric serum gastrin in Japanese with gastric hyperplastic polyps or mucosa. Gastroenterology 1996;110: polypoid-type early gastric carcinoma. Scand J Gastroenterol 20. Wallace JL, Cucala M, Mugridge K, Parente L. Secretagogue- 1993;28: specific effects of interleukin-1 on gastric acid secretion. Am J 34. Correa P. Human gastric carcinogenesis: a multistep and multi- factorial process first American Cancer Society Award lecture Physiol 1991;261:G559 G564. on cancer epidemiology and prevention. Cancer Res 1992;52: 21. Ruiz B, Correa P, Fontham ET, Ramakrishnan T. Antral atrophy, Helicobacter pylori colonization, and gastric ph. Am J Clin Pathol 35. Carneiro F, Taveira-Gomes A, Cabral-Correia A, Vasconcelos- 1996;105: Teixeira A, Barreira R, Cardoso-Oliveira M, Sobrinho-Simoes M. 22. Morris A, Nicholson G. Ingestion of Campylobacter pyloridis Characteristics of the gastric mucosa of direct relatives of pacauses gastritis and raised fasting gastric ph. Am J Gastroenterol tients with sporadic gastric carcinoma. Eur J Cancer Prev 1993; 1987;82: : Marshall BJ, Armstrong JA, McGechie DB, Glaney RJ. Attempt to 36. Ihamaki T, Sipponen P, Varis K, Kekki M, Siurala M. Characterisfulfill Koch s postulates for pyloric campylobacter. Med J Aust tics of gastric mucosa which precede occurrence of gastric malig- 1985;142: nancy: results of long-term follow-up of three family samples. 24. Ramsey EJ, Carey KV, Peterson WL, Jackson JJ, Murphy FK, Read Scand J Gastroenterol 1991;26: NW, Taylor KB, Trier JS, Fordtran JS. Epidemic gastritis with hypochlorhydria. Gastroenterology 1979;76: Received December 9, Accepted March 18, Gledhill T, Leicester RJ, Addis B, Lightfoot N, Barnard J, Viney Address requests for reprints to: Kenneth E. L. McColl, M.D., Uni- N, Darkin D, Hunt RH. Epidemic hypochlorhydria. BMJ 1985;290: versity Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland. e.m.el-omar@clinmed.gla.ac.uk; 26. Graham DY, Alpert LC, Smith JL, Yoshimura HH. Iatrogenic fax: (44) Campylobacter pylori infection is a cause of epidemic achlorhy- Supported by a grant from the Biomedical and Research Commitdria. Am J Gastroenterol 1988;83: tee of the Scottish Home and Health Department. 27. Peterson W, Lee E, Skoglund M. The role of Campylobacter pylo- The authors thank the staff of the Nuclear Medicine Department, ridis in epidemic gastritis with hypochlorhydria (abstr). Gastroen- Western Infirmary, for performing the 14 C-urea breath tests and Anterology 1987;89:1575. thea Dickson, Doreen Adams, and Amanda Agnew for technical assis- 28. Frommer DJ, Carrick J, Lee A, Hazell SL. Acute presentation of tance.