Helicobacter pylori infection is now firmly established

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1 GASTROENTEROLOGY 1998;114:50 57 The Acid Response to Gastrin Distinguishes Duodenal Ulcer Patients From Helicobacter pylori Infected Healthy Subjects DEREK GILLEN,* EMAD M. EL OMAR,* ANGELA A. WIRZ,* JOY E. S. ARDILL, and KENNETH E. L. MCCOLL* *University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland; and Queen s University, Belfast, Northern Ireland Background & Aims: Helicobacter pylori induced hypergastrinemia is accompanied by increased acid secretion in patients with duodenal ulcer (DU) but not in infected healthy volunteers. The aim of this study was to investigate the mechanism underlying this difference. Methods: Thirty-four H. pylori negative and 20 H. pylori positive healthy volunteers and 15 H. pylori positive patients with DU were studied. Maximal acid output and sensitivity to gastrin (gastrin concentration required to achieve 50% maximal acid output) were assessed by examining the dose response to gastrin 17. Inhibitory control was tested by comparing the maximal acid response to cholecystokinin octapeptide with that for gastrin 17. Results: Sensitivity to gastrin was similar in patients with DU (median, 69.5 ng L 1 ; range, ) and H. pylori negative healthy volunteers (median, 82.2 ng L 1 ; range, ); H. pylori positive healthy volunteers were less sensitive than either (164.5 ng L 1 ; range, 44.8 to 3360 ng L 1 ). Patients with DU had higher maximal acid output (51.2 mmol h 1 ; range, mmol h 1 ) than either infected healthy volunteers (37.8 mmol h 1 ; range, mmol h 1 ; P F 0.04) or uninfected healthy volunteers (35.3 mmol h 1 ; range, mmol h 1 ; P F 0.002). The maximal acid output in both groups of healthy subjects was similar. The proportion of maximal acid output to gastrin 17 achieved by cholecystokinin was similar in patients with DU (36.6%; range, 21.5% 58.2%) and H. pylori negative healthy volunteers (28.7%; range, 5.9% 85.8%). Conclusions: A combination of decreased sensitivity to gastrin in infected healthy volunteers and increased maximal acid secretory capacity in patients with DU underlies their different acid response to H. pylori induced hypergastrinemia. Helicobacter pylori infection is now firmly established as the major acquired factor in the pathogenesis of duodenal ulcer (DU) disease. 1,2 However, between 33% and 66% of western populations have this infection, 3,4 yet only approximately 10% 15% of the general population develop DU in their lifetime. 5,6 The reason why only a subgroup of H. pylori infected subjects develops DU remains unknown. Although different bacterial strains may partially explain this (in particular those expressing the CagA cytotoxin), 7,8 host and environmental factors are also likely to be important. Excessive acid secretion has long been recognized to play an important role in the pathophysiology of DU disease. 9 Furthermore, recent studies indicate that H. pylori infection stimulates hypersecretion of acid in patients with DU When compared with H. pylori negative healthy volunteers (HVs), H. pylori infected patients with DU have a sixfold increased acid response to stimulation with gastrin-releasing peptide (GRP) and a marked increase in basal acid output. 12,13 These exaggerated acid responses resolve after eradication of H. pylori. 12 The H. pylori induced hypersecretion of acid in the patients with DU is thought to be partly related to the infection stimulating increased release of gastrin from the antral mucosa. However, the degree of increase of serum gastrin is similar in H. pylori positive patients with DU and infected HVs, 14,15 yet in the latter the hypergastrinemia is not accompanied by the same degree of acid hypersecretion. We have previously reported that H. pylori positive HVs have little or no increase in basal acid output and that their acid response to GRP stimulation is only 50% of that seen in the patients with DU. 12,13 Thus, a key characteristic of the H. pylori positive patients with DU when compared with the infected HVs is a greater acid response to gastrin stimulation. There are at least three possible explanations for this difference in acid secretion in response to similar stimulating levels of gastrin. First, the patients with DU may have increased maximal acid secretory capacity. This maximal acid secretory capacity is thought to depend on Abbreviations used in this paper: C 50, concentration to give 50% of maximal acid output; DU, duodenal ulcer; ECL, enterochromaffinlike; E max, estimated maximal acid output; G-17, gastrin 17; HV, healthy volunteer; MAO, maximal acid output by the American Gastroenterological Association /98/$3.00

2 January 1998 H. PYLORI AND ACID RESPONSE 51 the function of two main oxyntic cell types. The first of these is the enterochromaffin-like (ECL) cell, whose secretion of histamine is predominantly influenced by gastrin from the antral G cell. 16 The other is the parietal cell, which is mainly stimulated to secrete acid by this ECL cell derived histamine, acting through the histamine H 2 receptor 20 and also possibly by direct action of gastrin. 19 Second, patients with DU may be more sensitive to the acid stimulatory effects of gastrin, i.e., achieve 50% of their maximal acid secretory capacity at a lower gastrin concentration. Third, there may be a failure of inhibitory control of oxyntic cell function in patients with DU. The inhibitory control of oxyntic cell function is thought to be mediated largely via the release of somatostatin from oxyntic mucosal D cells. 21 Cholecystokinin (CCK) can be used to investigate the integrity of the somatostatin-mediated inhibitory control pathway within the oxyntic mucosa because its activation of CCK-A receptors on corpus D cells stimulates local release of somatostatin. 22,23 CCK is also a potential powerful agonist of the CCK B/gastrin receptor of the oxyntic cells. 24 Consequently, impairment of the somatostatinmediated inhibitory control of oxyntic mucosal function results in the acid response to CCK approximating that to gastrin, as is seen when the CCK-A receptors on the oxyntic D cells are inhibited by specific CCK-A antagonists. 25,26 The ratio of maximal acid output (MAO) to CCK vs. MAO to gastrin may therefore be used as a measure of inhibitory control of oxyntic mucosal function. The aim of this study was to investigate whether the increased acid response to gastrin distinguishing H. pylori positive patients with DU from infected HVs was caused by differences in maximal acid secretory capacity, sensitivity to gastrin, or oxyntic inhibitory control. Materials and Methods Subjects Studied Fifteen H. pylori positive patients (12 men) with chronic DU disease were included in the gastrin 17 (G-17) study. Nine of them were smokers. Each had been confirmed to have DU disease by endoscopic examination within the past 2 years, and current H. pylori infection was confirmed by the [ 14 C]urea breath test. All patients were symptomatically healed using a 6-week course of ranitidine, 150 mg twice per day (12 patients), or omeprazole, 20 mg twice per day (3 patients). In addition, before the secretory studies, antisecretory therapy was stopped at least 2 weeks before the acid secretion tests. Twenty H. pylori positive HVs (15 men, 10 of them smokers) and 34 H. pylori negative HVs (25 men, 13 of them smokers) were also studied. None of these volunteers was taking any medication and none reported major gastrointestinal symptoms. Their H. pylori status was determined using the [ 14 C ]urea breath test. In addition, 21 H. pylori negative HVs, 12 H. pylori positive HVs, and 9 patients with DU had a further CCK-8 acid secretion study on a separate morning. All groups were matched for age, sex, and body weight. The patients were recruited via the Gastroenterology Department at The Western Infirmary, and the volunteers were recruited by advertising in the hospital s catchment area. Methods Sensitivity to gastrin was determined by measuring the acid output in response to increasing concentrations of G-17 and calculating the concentration of plasma gastrin giving 50% of the maximal acid response (C 50 ). The MAO (E max )to G-17 was used as a measure of maximal acid secretory capacity. The ratio of the MAO to CCK over the maximal acid output to G-17 was used as a measure of somatostatin-mediated oxyntic inhibitory control. This is possible because the similar, short half-lives of these hormones mean that they are in steady state for similar time periods. All subjects reported at 9 AM after a 12-hour fast. A 16F nasogastric tube (Andersen Inc., New York, NY) was passed, and its position in the dependent part of the stomach was checked using the water recovery test. 27 After the stomach was emptied, intermittent suction was applied using an intermittent suction unit (Ohmeda, Columbia, MD) that applies suction for 20 seconds in each 32-second cycle. A 30-minute acid collection was obtained basally, then sequentially during 30-minute infusions of G-17 at doses of 7, 20, 60, 180, and 800 pmol kg 1 h 1. On a separate morning, the same procedure was repeated after a 30-minute basal acid collection followed by sequential 30-minute infusions of CCK-8 at doses of 7, 20, 60, and 120 pmol kg 1 h 1. It has been shown previously that no fade of response occurs at either of these sets of peptide doses over these time periods. 28 Some subjects only participated in the G-17 dose-response study and did not undertake the CCK-8 study. Blood samples were collected each morning for gastrin determination, both basally and at the end of each infusion period. The plasma was stored at 20 C. These two tests were varied in random order. The volume of each acid collection was noted, and its hydrogen ion concentration was measured by titration with 0.1 mol/l sodium hydroxide to ph 7.0 using an autotitrator (Radiometer ETS 822; Radiometer, Copenhagen, Denmark). The acid output was then calculated by multiplying the volume by the hydrogen ion concentration. G-17 was purchased from Peninsula Laboratories (Belmont, CA) and CCK-8 from Genosys (Cambridge, England) as aliquots of freeze-dried lyophilized powder. Subsequent preparation was performed under sterile conditions by the Western Infirmary Pharmacy Department. Each aliquot was dissolved in a small volume of ammonium bicarbonate, then made up into a stock solution. Vials containing 100 g of G-17 or CCK-8 were prepared and stored at 20 C until the day of the study. For each study, the content of the vial was further diluted in

3 52 GILLEN ET AL. GASTROENTEROLOGY Vol. 114, No % sodium chloride solution containing 1% human serum albumin (Scottish National Blood Transfusion Service, Carluke, Scotland). The peptide solution was filtered through a m low-protein-binding bacterial filter (Gelman Sciences, Northampton, England) before the final concentrations of infusate were prepared. Gastrin levels were measured by radioimmunoassay using antiserum R98, which has a sensitivity of 5 ng L 1 and detects G17 and G34, in both their sulfated and unsulfated forms, with equal affinity. 29 Analysis C 50 and E max were calculated by computer-generated Langmuir plot (Clydesoft, University of Glasgow, Glasgow, Scotland) by plotting plasma gastrin concentration against acid output in a least-squares regression model. Statistics Statistical analysis was performed using the Mann Whitney U test. A P value of 0.05 was considered significant. The study was approved by the West of Glasgow University Hospitals National Health Service Trust Ethical Committee, and all subjects gave written, informed consent. Results Basal Plasma Gastrin and Basal Acid Output Median basal gastrin concentration increased to a similar extent in the H. pylori positive HVs (25 ng L 1 ; range, ng L 1 ) and H. pylori positive DUs (30 ng L 1 ; range, ng L 1 ) compared with the H. pylori negative HVs (20 ng L 1 ; range, 5 42 ng L 1 ; P 0.04 and 0.01, respectively; Figure 1). The median basal acid secretion in the H. pylori negative HVs (2.4 mmol h 1 ; range, mmol h 1 ) was similar to that of the H. pylori positive HVs (3.0 mmol h 1 ; range, mmol h 1 ; P NS). The median basal acid output in the patients with DU was considerably higher than in either of these groups (12.7 mmol h 1 ; range, mmol h 1 ; P and P , respectively; Figure 1). C 50 The patients with DU and H. pylori negative HVs were similar with respect to their sensitivity to gastrin. The C 50 in the former was 69.5 ng L 1 (range, ng L 1 ) and in the latter was 82.2 ng L 1 (range, ng L 1 ). The H. pylori positive HVs were less sensitive to gastrin than either the patients with DU or H. pylori negative HVs. The median C 50 of the H. pylori positive HVs was ng L 1 (range, 44.8 to 3360 ng L 1 ), which was significantly higher than that of either the H. pylori negative HVs (P 0.003) or patients with DU (P ; Figure 2). E max The median E max in the H. pylori negative HVs (35.3 mmol h 1 ; range, mmol h 1 ) was Figure 1. Basal plasma gastrin concentration and basal acid output in H. pylori negative HVs, H. pylori positive HVs, and patients with DU. Median of values indicated by horizontal line. Basal gastrin concentration is greater in both H. pylori positive HVs and patients with DU than in H. pylori negative HVs (P 0.04 and P 0.01). Basal acid output is increased in patients with DU compared with both H. pylori negative HVs (P ) and H. pylori positive HVs (P ). Figure 2. Sensitivity (C 50 ) to gastrin in H. pylori negative HVs, H. pylori positive HVs, and patients with DU. The H. pylori positive HVs are significantly less sensitive than the H. pylori negative HVs (P 0.003) and patients with DU (P ).

4 January 1998 H. PYLORI AND ACID RESPONSE 53 similar to that of the H. pylori positive HVs (37.8 mmol h 1 ; range, mmol h 1 ). The median E max in the patients with DU (51.2 mmol h 1 ; range, mmol h 1 ) was significantly higher than that of either the uninfected HVs (P 0.002) or the H. pylori infected HVs (P 0.04; Figure 3). CCK-8 Stimulated Acid Output In most subjects in each group, acid output increased initially in response to CCK-8 and then decreased with higher doses of infusate. The dose of CCK-8 at which the maximal acid response occurred was similar in each group. The MAOs to CCK-8 in the H. pylori negative (11.4 mmol h 1 ; range, mmol h 1 ) and H. pylori positive HVs (6.6 mmol h 1 ; range, mmol h 1 ) were not significantly different. The MAO output to CCK-8 in the patients with DU (18.0 mmol h 1 ; range, mmol h 1 ) was significantly greater than that of either the H. pylori negative (P 0.01) or H. pylori positive HVs (P 0.008). Proportion of G-17 MAO Achieved by CCK The ratio of the MAO to CCK-8 to the MAO to G-17 in the H. pylori negative HVs (median, 28.7%; range, 5.9% 85.8%) was not significantly different from that of the infected HVs (15.8%; range, 0% 46.9%) or the patients with DU (36.6%; range, 21.5% 58.2%). However, the ratio for the patients with DU was significantly greater than that for the infected HVs (P 0.02; Figure 4). Discussion Numerous studies have shown that H. pylori infection reversibly increases basal and stimulated serum Figure 3. MAO (E max ) to G-17 in H. pylori negative HVs, H. pylori positive HVs, and patients with DU. The patients with DU have a significantly greater estimated maximal acid secretion than the H. pylori negative HVs (P 0.002) or H. pylori positive HVs (P 0.04). Figure 4. Proportion of G-17 MAO achieved by CCK-8 in H. pylori negative HVs, H. pylori positive HVs, and patients with DU. The patients with DU had a significantly greater proportion than the H. pylori positive HVs (P 0.02) but not greater than the H. pylori negative HVs. gastrin concentrations and that the degree of increase is similar in patients with DU and HVs. 14,15,30 33 However, it has been shown previously that both basal and GRP-stimulated acid secretion is considerably greater in H. pylori positive patients with DU than in infected HVs. 12,13 The patients with DU, therefore, have a greater acid response to gastrin stimulation than H. pylori positive HVs. The aim of this study was to determine whether this is caused by differences in maximal acid secretory capacity, sensitivity to gastrin, or failure of gastric body inhibitory control. The basal gastrin and acid data in this study (Figure 1) show the increased acid response to gastrin characteristic of the patients with DU. 12,13,34 36 The basal gastrin was increased to a similar extent in the H. pylori positive patients with DU and infected HVs, yet the median basal acid output in the former was fourfold higher than the latter. Furthermore, in the present study, basal acid secretion was found to be similar in H. pylori positive and negative HVs, despite the former having significantly higher basal gastrin concentrations. Our G-17 dose-response studies indicate that the major reason for the different acid response to gastrin between the H. pylori positive HVs and patients with DU is their different sensitivity to gastrin. The latter were more than twice as sensitive to gastrin as the former. In addition, our data indicate that the difference in sensitivity between the H. pylori positive HVs and patients with DU is caused by the former having a reduced sensitivity compared with the true normals (H. pylori negative HVs), whereas the patients with DU have a similar sensitivity to that of the true normals. This observation is consistent with the finding by Pounder s group of inappropriate hypergastrinemia in asymptomatic healthy subjects infected with H. pylori. 37

5 54 GILLEN ET AL. GASTROENTEROLOGY Vol. 114, No. 1 Figure 5. Median plasma gastrin concentration vs. median acid output in H. pylori negative HVs ( ), H. pylori positive HVs (Q), and patients with DU (W). It has been suggested, in the past, that to calculate sensitivity to gastrin, one must make a basal correction to the acid secretion data to adjust for the increased basal acid secretion inherent to DU disease. 38,39 The data generated in that way could then be plotted in a classic dose-response curve of pentagastrin dose against acid secreted. However, it is now known that endogenous gastrin is the most important stimulus to basal acid secretion both in humans 40,41 (C. Beglinger, personal communication, August 1997) and in animals Basal correction will therefore artificially reduce the effective acid response in those individuals with high intrinsic sensitivity to endogenous gastrin. We have therefore examined sensitivity by plotting the serum concentration of gastrin both basally and during G-17 infusion against the actual acid secreted (Figure 5). The radioimmunoassay used makes this possible as it detects the infused G-17 and endogenous basal gastrin (mainly gastrin 34) with equimolar affinity. 29 Several previous studies using histamine and pentagastrin have suggested that there is no difference in sensitivity to stimulation between DUs and controls. 36,45,46 Other studies have shown an increased sensitivity in patients with DU to histamine, pentagastrin, and meal stimulation The data in the present study both support the latter studies and extend them by indicating that the difference in sensitivity to gastrin stimulation lies between the H. pylori infected HVs and both the patients with DU and uninfected controls. The previously discordant results may be explained by differing proportions of infected to uninfected subjects within the control groups because the H. pylori negative HVs in this study were not significantly different from the patients with DU. This observation that patients with DU do not differ significantly from true normals may also explain why previous studies have shown no difference in sensitivity to gastrin in patients with DU before and after H. pylori eradication. 11,51 The cause of this difference in sensitivity between the groups is at present unclear. There may be a role for a host influence. This is supported by our observation that the sensitivities of all but 1 of the infected HVs and patients with DU lie within the range of true normal (i.e., H. pylori negative HVs) values (Figure 2). The bacterium itself may also contribute to the difference in sensitivity between the H. pylori positive HVs and patients with DU. In particular, the infection may contribute to the lowered sensitivity in some of the H. pylori positive HVs. It is recognized that a subgroup of H. pylori infected subjects develops a body-predominant gastritis with associated marked impairment of acid secretion. 52 Indeed, 1 of our H. pylori positive HVs had markedly impaired acid secretion consistent with this defect. The normal sensitivity to gastrin in the patients with DU may therefore be explained by the observation that in these subjects body mucosa is relatively uninvolved by H. pylori gastritis. 53 In contrast, the H. pylori infected nonulcer subjects tend to have more involvement of the body mucosa, 52,54 which may impair sensitivity to gastrin. The mechanism of such a possible influence for body gastritis remains unclear. However, one may suggest that the function of either the ECL or parietal cell, or both, could be impaired by the action of either bacterial products or of cytokines, such as interleukin 1. 58,59 The present study also indicates that a proportion of the increased acid response to gastrin between the patients with DU and H. pylori positive HVs can be attributed to a higher maximal acid secretory capacity in the former. We have shown that the patients with DU have a higher MAO than both of the healthy control groups. This is consistent with previous reports 34,36,45 that indicated that patients with DU had a higher maximal acid secretion than healthy subjects. Furthermore, it extends these reports by showing that the difference between patients with DU and healthy subjects does not depend on the H. pylori status of the HVs. The cause of the higher maximal acid secretory capacity in the patients with DU is unclear. It may be a host factor, a hypothesis supported by maximal acid secretion values of all but 2 of the 15 patients with DU falling within the range of the true normal uninfected controls. There may also be a role for H. pylori. This could be mediated by the chronic H. pylori induced hypergastrinemia exerting a trophic effect on the oxyntic mucosa in a manner analogous to that seen in the Zollinger Ellison syndrome. 60 Although the H. pylori positive HVs have a similar degree of hypergastrinemia, 14,15 their more

6 January 1998 H. PYLORI AND ACID RESPONSE 55 marked body-predominant gastritis 52,54 may mask any trophic effect. This hypothesis is consistent with the previous observations that MAO is reduced by H. pylori induced body gastritis. 52,61 The increased acid secretory capacity in the patients with DU could be caused by an increased number or increased functional activity of either the parietal cells 62,63 or ECL cells or of both. We have also investigated the possibility of differences in inhibitory control of oxyntic mucosal function as an explanation of the differences in acid response to gastrin between the patients with DU and infected HVs. This was examined by comparing the acid response to CCK and to G-17. CCK and gastrin have been shown to be equipotent stimuli to acid production in isolated canine parietal cells, 24 both acting on the gastrin/cck-b receptor. However, in the whole animal, CCK acts as a partial agonist with weak efficacy in acid secretion This may be explained by the fact that CCK stimulates oxyntic mucosal D cells 23 to release somatostatin, which exerts a local paracrine inhibitory effect on oxyntic cell function. 21,71 This inhibitory effect of CCK is mediated via CCK-A receptors on the fundic D cells. CCK-A receptor antagonist blockade of this inhibitory pathway results in the acid stimulatory effect of CCK approximating that of G ,26 If there were failure of oxyntic inhibitory control in the patients with DU, they would have a significantly higher ratio of MAO to CCK-8 vs. MAO to G-17 than the true normals (H. pylori negative HVs), because their MAO to CCK would more closely approximate that to maximal G-17 stimulation. 25,26 No such difference was observed. Indeed, the only significant difference shown was between the infected HVs and the patients with DU. This can be attributed to our demonstration that the H. pylori positive HVs have a reduced sensitivity to gastrin (i.e., CCK B receptor) stimulation. In summary, we have observed that the H. pylori positive patients with DU have a fourfold higher basal acid output than H. pylori positive HVs, despite both groups having similar gastrin levels. Our investigations indicate that this is caused by the combination of a 1.4-fold increased maximal acid secretory capacity in the former plus a 2.4-fold decreased sensitivity in the latter. We have found no evidence of impairment of oxyntic inhibitory control in the patients with DU. Differences in acid output caused by a difference in sensitivity will be most marked at the lower end of the gastrin-acid dose-response curve, and this is apparent in Figure 5. This is consistent with the observation that the acid response to basal gastrin concentrations is increased fourfold in the patients with DU compared with H. pylori positive HVs, whereas the acid response to the higher GRP-stimulated gastrin level is increased only twofold, as we have previously reported. 12,13 In conclusion, the increased acid response to gastrin characteristic of H. pylori positive patients with DU compared with that of infected HVs is caused by the combination of decreased sensitivity to gastrin stimulation in the latter and increased maximal acid secretory capacity in the former. References 1. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1: Graham DY. Campylobacter pylori and peptic ulcer. Gastroenterology 1989;96: Graham D, Klein PD, Opekun AR, Boutton TW. 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