Digestion 1992;51(suppl 1): 11-16

S. Rune

Helicobacter pylori, Peptic Ulcer

Department of Gastroenterology, Glostrup Hospital. Glostrup. Denmark

Disease and Inhibition of Gastric Acid Secretion

Key Words Helicobacter pylori Gastric acid secretion Gastric acid inhibition Duodenal ulcer Omeprazole

Abstract Recent studies have been reviewed to establish the possible importance of the interaction between Helicobacter pylori infection and gastric acid secretion. H. pylori infection results in increased gastrin release, but this does not lead to gastric acid hypersecretion and gastrin normalizes after eradication of the infection. An optimal, well-tolerated treatment strategy against H. pylori infection has not yet been clearly defined. One poten­ tially useful approach may be to improve the antibacterial effi­ cacy of antibiotics by effectively regulating gastric acidity. Hr reccptor antagonists have no effect against H. pylori infection, while omeprazole (an acid pump inhibitor) appears to have a bacteriostatic action. Combination therapy with omeprazole and amoxycillin has been found to eradicate H. pylori in 50-80% of patients with duodenal ulcer, leading to a significant reduction in ulcer recurrence.

that eradication of H. pylori in a high percent­ age of patients is followed by a significant reduction in the rate of ulcer recurrence. How­ ever, although eradication of //. pylori in patients with duodenal ulcer is now an im­ portant goal, an effective treatment strategy with minimal side-effects has yet to be defined. The interaction between H. pylori infection and gastric acid secretion, which may have several implications, is of possible therapeutic importance.

S. Rune Department of Gastroenterology Glostrup Hospital DK-2600 Glostrup (Denmark)

© 1992 Karger AG. Basel 0012-2823/92/ 0517-0011 $ 2.75/0

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Since the introduction of effective acidinhibitory drugs, healing of peptic ulcers has not usually been a problem. Unfortunately, peptic ulcer disease is associated with a high rate of recurrence, towards which improve­ ments in treatment must be directed. Recently, it has been shown that Helico­ bacter pylori infection of the stomach is one important ulcerogenic factor. While the patho­ genetic mechanism(s) by which H. pylori be­ comes ulcerogenic is not clear, it is apparent

Log CFU 10

Fig. 1. Survival rate of bacteria in acid alone. CFU = colonyforming unit. Published with per­ mission front [3J. Log CFU 10

Fig. 2. Survival rate of bacteria in acid plus urea. CFU = colonyforming unit. Published with per­ mission from [3).

Survival of Helicobacter pylori in a High-Acidity Environment Owing to the high concentration of hydro­ chloric acid, gastric juice has a strong bacteri­ cidal effect on nearly all bacteria, including H. pylori [11. Nevertheless. II. pylori survives in the stomach and colonizes the gastric mucosa of patients with peptic ulcer disease and gastritis [2]. This special ability of H. pylori



can probably be explained by the fact that the bacterium produces a potent urease, enabling it to hydrolyse sufficient urea to produce ammonia, which neutralizes hydrogen ions in its immediate micro-environment. The survival of H. pylori in an acid environment depends on the presence of urea (figs. 1 and 2) [3j. Also, the movement of hydrogen ions through mucus infected with H. pylori is reduced, when com­ pared with uninfected mucus [4].

II. pylori and Peptic Ulcer

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Helicobacter pylori, Serum Gastrin and Gastric Acid Secretion Meal-stimulated serum gastrin levels are higher in patients with duodenal ulcer, as a group, than in non-ulcer controls. Recently, it has been shown that patients with duodenal ulcer who are H. pylori-positive have high basal and meal-stimulated serum gastrin levels, both of which fall after eradication of H. pylori (fig.3 and table 1) [6. 7]. The bombesin-stim-

Table 1. Gastric acid output and scrum gastrin before and after eradication of Helicobacter pylori in patients with duodenal ulcer (n = 10)

Gastrin (pmol/min/litrc) Basal acid output (mmol/hour) Peak acid output (mmol/hour)

Before eradication of H. pylori

After eradication of H. pylori



4 .1




Published with permission from [9].

Serum 9astrin (ng/litre)

*------ * H. pylori-positive x------ x H. pylori-negative

Time (minutes) Fig. 3. Scrum gastrin concentrations before and after eradication of Helicobacter pylori in patients with duodenal ulcer. Published with permission from [7].

ulated serum gastrin release also falls after eradication of H. pylori (fig.4) [8]. Even though serum gastrin levels return to normal, suppression of H. pylori does not seem to alter gastric acid secretion - whether measured after exogenous stimulation with pentagastrin or after endogenous stimulation by a meal [9]. The mechanisms behind these findings are not known, but the results seem to exclude the immediate explanation that ammonia pro­ duced by H. pylori neutralizes acid at the antral epithelial surface, thereby reducing the pHdependent inhibition of serum gastrin release. Also, the number of antral G-cells has been found to be unchanged in patients with II. pylori infection [!()]. The clinical relevance of this exaggerated serum gastrin response associated with H. pylori is unknown. Its importance in peptic ulcer disease is doubtful, as long as gastric acid secretion is unaffected by the increased serum gastrin - a point that needs to be studied more extensively.


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Another interesting aspect of the relation­ ship between //. pylori and gastric acid secre­ tion is the surprisingly low incidence of antral colonization with the bacterium in patients with pernicious anaemia. In a prospective study, only 11% of antral biopsies from such patients were H. pylori-positive, compared with 71% in controls [5]. Thus, it seems possi­ ble that gastric acid contributes to a suitable environment for H. pylori, although an alter­ native explanation may be that the auto­ immune gastritis in patients with pernicious anaemia makes the stomach less susceptible to colonization with H. pylori.

Table 2. Effects on Helicobacter pylori infection before and after 4 weeks' treatment with omeprazole or


Number of patients No or only occasional bacteria Scattered or numerous bacteria in most fields

Omeprazole. 20 mg once daily

Ranitidine. 150 mg twice daily





76 49% 51%

76 98% 4%

79 45% 56%

79 57% 43%

Published with permission from [16].


*------ * Before eradication


x------x After eradication


Table 3. Effects on Helicobacter pylori infection before and after 4 weeks' treatment with omeprazole. 20 mg once daily, and 4 weeks after the end of treatment (n =26) 117|

II. py/on-positive patients (%)


End of treatment

4 weeks after end of treatment




Copyright 1991 John Wiley & Sons, Ltd. Published by permission of John Wiley & Sons. Ltd.

Fig. 4. Bombesin-stimulated serum gastrin release

in patients with duodenal ulcer before and after eradica­ tion of Helicobacter pylori. Published with permission from |8|.

Effect of Acid-Inhibitory Drugs on Helicobacter pylori As already stated. H. pylori is extremely well adapted for survival in an acid environ­ ment. The possible influence of acid-inhibitory drugs on H. pylori is therefore of interest. There seems to be general agreement that H:-receptor antagonists do not have any effect



on H. pylori infection 111 ]. There is. however, controversy regarding the use of omeprazole, as not all investigators have obtained the same results. In two controlled studies [ 12. 13|. none of the patients treated with omeprazole alone was H. pylori-negative after treatment, while in several other studies [ 14—17J a significant proportion of patients treated with ome­ prazole, 20-40 mg daily for 4 weeks, became H. pylori-negative (tables 2 and 3). The most probable explanation for this apparent dis­ agreement is that omeprazole treatment sup­ presses //. pylori, but does not eradicate it. Thus, clearance may be observed at the end of treatment, but follow-up studies some weeks later may show no effect.

H. pylori and Peptic IJlcer

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Bombesin (pmol/kg/hour)

The mechanism behind the bacteriostatic effect of omeprazole treatment is not known. It may be a direct effect of omeprazole on H. pylori or an indirect effect caused by the change in the micro-environment of the bacterium.

Synergistic Effect of Gastric Acid Inhibition and Antibiotic Treatment of Helicobacter pylori Infection Despite high activity in vitro, single-drug treatment of //. pylori infection has a poor out­ come in most studies [ISj. This is most prob­ ably due to problems with drug delivery to the gastric mucosa, caused by a decrease in the pharmacological activity of antibiotics in the acidic gastric juice and by unfavourable trans­ port of antibiotics into the mucus and mucosa. As shown in table 4. the efficacy of many anti-

Table 4. Minimal inhibitory concentration 90:s at different pH values

Tetracycline Metronidazole Penicillin Ampicillin Erythromycin

pH 7.5

pH 6.5

pH 5.5

0.12 2.00 0.03 0.06 0.06

0.25 2.00 0.50 0.25 2.(HI

0.50 2.00 0.50 0.50 8.00

biotics is extremely pi 1-dcpcndcnt [19, 20]. Thus, there is a rationale for combination ther­ apy with acid-inhibitory drugs and antibiotics in the treatment of II. pylori infection. Recently, a controlled study of combination therapy with omeprazole and amoxycillin in patients with duodenal ulcer showed eradica­ tion of II. pylori in 54% of patients 4 weeks after cessation of therapy (table 5) [12]. In a similar study, the same combination therapy resulted in an eradication rate of 82% [13]. In both studies, the recurrence rate of duodenal ulcer 6 months [ 121 and 9 months [13] after cessation of treatment was significantly lower in the patients treated with combination ther­ apy (30% and 0%, respectively) than in those treated with omeprazole alone (64% and 45%, respectively). This shows that it is eradication of //. pylori that is the important factor for the prolonged remission of duodenal ulcer. Ungc et al. have pointed out that the mechanisms behind the pronounced eradication of H. pylori with combination therapy arc unclear, and that there are several possibilities; for example, the optimal pH for amoxycillin is closer to the luminal pi I of the stomach during omeprazole treatment, and the lower volume of gastric juice during such treatment leads to a higher concentration of amoxycillin in the stomach [12|. Elevated intragastric pH might make H. pylori more susceptible to antibiotic attack.

Table 5. Effect of a combination of omeprazole and amoxycillin tin eradication of Helicobacter pylon 4 weeks and 6 months after cessation of therapy, or at the last patient visit

Eradication of Helicobacter pylori

Omeprazole/placcbo Omcprazolc/amoxycillin

4 weeks

6 months, or at last visit

3/76 (4% ) 84/157 (54%)

81/151 (54%)

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Results not obtained with omeprazole/placcbo at 6 months during this study [ I2|. Copyright 1991 John Wiley & Sons. Ltd. Published by permission of John Wiley & Sons. Ltd.

Conclusions Ammonia produced by H. pylori neutral­ izes hydrogen ions in the gastric mucus, and may protect the bacterium from the bacteri­ cidal effect of gastric acid. H. pylori infection is associated with an exaggerated serum gastrin release, but gastric acid output is not altered by its suppression/eradication. Treatment with omeprazole, but not IT-receptor antagonists.

suppresses II. pylori, but does not eradicate it. The mechanism behind this bacteriostatic effect is not yet known. I lighly effective gastricacid inhibition appears to improve the efficacy of antibiotics against H. pylori. Combination therapy with omeprazole and amoxycillin eradicates H. pylori in 50-80% of patients, and reduces the relapse rate of duodenal ulcer significantly.

1 Giannella RA. Broitman SA. Zamcheck N: Gastric acid barrier I» ingested microorganisms in man: studies in vivo and in vitro. Gut 1972:13:251-256. 2 Marshall B.I. Warren JR: Unidenti­ fied curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984:1: 1311-1315. 3 Marshall BJ. Barrett U . Prakash C. McCallutn RW .Guerrant RL. Urea protects Helicobacter pylori from the bactericidal effect of acid. Gas­ troenterology 1990:99:697-702. 4 Thomsen L. Tasman-Jones C. Morris A. Wiggins P. Lee S. Forlong C: Ammonia produced by Campylobacter pylori neutralizes II moving through gastric mucus. Stand .1 Gastroenterol 1989:24: 761-768. 5 Fong T-L. Dooley CP. Dehcsa M. el at: Helicobacter pylori infection in pernicious anemia: a prospective controlled study. Gastroenterology 1991:100:328-332. 6 Levi S. Bcardshall K. Haddad G. Playford R. Ghosh P. Calam J: Campylobacter pylori and duodenal ulcers: the gastrin link. Lancet 1989: 1:1167-1168. 7 McColl KEL. Fullarton GM. Nujumi AM. Macdonald AM. Brown I t- Hilditch TE: Lowered gastrin and gastric acidity after erad­ ication of Campylobacter pylori in duodenal ulcer (letter). Lancet 1989;2:499-500.

8 Graham DY. Opekun A. Lew GM. Klein PD. Walsh JH: Helicobacter pylori-associated exaggerated gas­ trin release in duodena) ulcer patients. Gastroenterology 1991: 100:1571-1575. 9 Moss S. Aycsu K. Li SK. Calam J: Gastrin, gastric acid and pepsin responses during intragaslric titra­ tion in duodenal ulcer patients: effect of suppressing Helicobacter pylori. Gut !991:32:AI206-AI207. 10 Graham DY. Lew GM. Lechago J: Helicobacter pylori related increase in plasma gastrin: what is status of the antral G cells in man? Gastro­ enterology I991:100:A75. 11 Blanco M. Pajares JM. Jimenez ML. Lopez-Brea M: Effect of acid inhibition on Campylobacter pylori. Scand J Gastroenterol 1988:23 (suppl 142): 107-109. 12 Unge P. Eriksson K. Bergman B. et al: Abstract book of VI Interna­ tional Workshop on Campylobacter. Helicobacter and related organisms. Sydney. Australia. 1991. 13 Baycrdorffcr E. Mannes GA. Som­ mer A. ct al: Presented at 46. Tagung der Deutschen Gesellschaft für Vcrdauungs- und Stoffwechsel­ krankheiten. Mannheim. Germany. September 1991. 14 Daw MA. Deegan P. Beattie S. Leen E. Keane CT. O'Moriain C: Suppression of Helicobacter pylori during the clinical use of omepra­ zole. Gut 1990:3 LA 1199.

15 Vigncri S. Termini R. Scialabba A. el al: Efficacy of omeprazole in healing duodenal ulcer and eradi­ cating Helicobacter pylori from gas­ tric mucosa. Sydney. World Con­ gresses of Gastroenterology. 1990. p. 928. 16 Hui WM. Lam SK. Ho J. el al: Effect of omeprazole on duodenal ulcer-associated antral gastritis and Helicobacter pylori. Dig Dis Sci 1991:36:577-582. 17 Louw JA. Zak J. Lastovica A. Jaskiewicz. Lucke W. Marks IN: Omeprazole may clear, but does not eradicate. Helicobacter pylori. Sydney. VI International Workshop on Campylobacter. Helicobacter and related organisms. 1991. 18 Axon ATR: Campylobacter-Ther­ apy review . Scand J Gastroenterol 1989:24(suppl l60):35-38. 19 McNulty CAM: Bacteriological and pharmacological basis for the treat­ ment of Campylobacter pylori infec­ tion: in Rathbonc BJ. Ileatlcy RV (eds): Campylobacter pylori and gastroduodenal disease. Oxford. Blackwell Scientific Publications. 1989. pp. 209-216. 20 Westhlom TU . Duriex DE: En­ hancement of antibiotic concentra­ tions in gastric mucosa by I L-rcccptpr antagonist. Implication for treat­ ment of Helicobacter pylori infec­ tions. Dig Dis Sci 1991:36:25-28.



II. pylori and Peptic Ulcer

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Helicobacter pylori, peptic ulcer disease and inhibition of gastric acid secretion.

Recent studies have been reviewed to establish the possible importance of the interaction between Helicobacter pylori infection and gastric acid secre...
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