There is now convincing evidence that Helicobacter pylori (H. pylori) infection plays an important part in the pathogenesis of peptic ulcer disease. More than 95% of patients with duodenal ulcer (DU)¹⁾ and 85% of patients with gastric ulcer (GU) have H. pylori infection of the gastric antrum, and eradication of this reduces the ulcer relapse rate²⁾. The way in which the chronic H. pylori infection of the gastric antrum predisposes to peptic ulceration is umclear but stimulation of excessive gastrin release, with resulting gastric hyperacidity, may be important especially in DU formation. It has recently been shown that patients with the infection have raised serum gastrin concentrations³⁾ which fall when the infection has been cleared^4,5). In addition, eradication of H. pylori infection results in a fall of 27–33% in the basal gastrin concentration and a fall of 30–58% in the integrated gastrin response to a meal⁶⁾. Similar results have been reported by several investigators^3,6–10,18). Because this increase in the serum gastrin concentration is associated with raised intragastric acidity after meals⁴⁾, gastrin may be the link between chronic H. pylori infection and peptic ulcer, especially DU disease^3,7). The mechanism by which chronic infection of the antral mcosa with H. pylori results in increased gastrin release is not known, but several hypotheses have been published explaining the H. pylori-associated hypergastrinemia.

In an attempt to clarify the relationship between the chronic H. pylori infection and the serum gastrin, we have measured serum levels of the gastrin before and after the eradication of H. pylori infection.

All of the 127 patients studied, who had either GU of DU, were effectively treated with ranitidine and mylanta for 4- to 6-week without any significant side reactions, and active ulcer craters were not found in all patients on the follow-up endoscopy. The first group patients were infected by H. pylori initially, but none had antral H. pylori both in microscopic and histologic examination of biopsy specimens after 4-week treatment of metronidazole and TDB (table 2 & 3). However the second group, who were also H. pylori-positive at the beginning of the study and were given only ranitidine and mylanta, all the patients were still infected by the organism on repeated examination even though ulcers were completely healed (Table 2 & 3). These date suggest that H₂-receptor antagonist and antacid do not have any antibacterial action against H. pylori and the combination therapy of metronidazole and TDB for 4 weeks is highly effective for eradication of H. pylori from the mucosa. The third group, initially free from H. pylori infection, none of the patients was infected by the organism during the study (Table 2 & 3).

Patients infected by H. pylori had significantly higher fasting serum gastrin concentrations than those negative for the organism. Serum gastrin concentrations of GU patients in the first group were 129.3±47.0 pg/ml (range 82.4–225.7 pg/ml) and those in the second group were 118.4±51.2 pg/ml (range 62.2–185.8 pg/ml). H. pylori-negative GU patients had significantly lower level of serum gastrin (range 45.6–168.7 pg/ml, 69.8±38.0 pg/ml) than H. pylori-positive GU patients. (p<0.05) (Table 3). Similar results have also been found in patients with DU: 108.3±35.0 pg/ml (range 49.4–197.2 pg/ml) in the first group and 85.4+35.1 pg/ml (range 34.5–167.4 pg/ml) in the second group, but the gastrin level of H. pylori-negative DU patients, the third group, was 55.1±17.6 pg/ml (range 40.6–98.7 pg/ml) ((p<0.05). (Table 3).

In the 12 GU patients with successful eradication of H. pylori, there was a significant fall in the fasting serum gastrin concentration from 129.3±47.0 pg/ml to 63/7±21.6 pg/ml after treatment (p<0.05) (Table 3, Fig. 1). In the 46 DU patients, the result was similar as in the GU: 108.3±35.0 pg/ml to 66.5±21.9 pg/ml after eradication (p<0.05) (Table 3, Fig. 1). In comparing results before and after eradication of the organism in the first group patients, serum gastrin concentrations fell significantly from 112.7±38.2 to 66.0±21.6 pg/ml (p<0.01) (Table 3, Fig. 1). Incontrast, fasting serum gastrin concentrations of the second group patients, in whom the H. pylori was not eradicated, were increased even though the difference was not statistically significant (pre-treatment value: 99.5±45.3 pg/ml and post-treatment value: 112.9±49.7 pg/ml)(Table 3, Fig. 2). In the third group, there was no change in the fasting serum gastrin concentration, with pre-treatment value being 63.2±31.1 pg/ml and post-treatment value being 63.4±30.0 pg/ml (Table 3, Fig. 3).

Epidemiological evidence of a relation between colonization of the gastric antrum with H. pylori and DU disease consists of the high prevalence of H. pylori colonization in most of DU patients¹¹⁾, the longer remissions of the disease obtained with treatments that suppress or eradicate H. pylori infection than with those that do not¹²⁾, and the finding that, after eradication of H. pylori, ulcers rarely recur before reinfection with the organism^2,13,14).

Patients with DU disease have higher gastric acid secretion, both basal and pentagastrin-stimulted, and also tend to have higher peak postprandial gastrin response than normal subjects. It has been shown that a low intragastric pH inhibits antral gastrin release less effectively in patients with DU disease than in normal subjects¹⁵⁾.

Before evaluating effects of H. pylori infection on the change of serum gastrin concentration, we examined any possible influences of 4- to 6-week treatment of H₂-receptor antagonist (ranitidine) and antacids (mylanta) on serum gastrin levels. There was no change in fasting serum gastrin concentrations between the pre-treatment and the post-treatment period (63.2±31.1 pg/ml vs 63.4±30.0 pg/ml0. These observations suggest that short-term treatment with either H₂-receptor antagonists or antacids does not have an influence on serum gastrin concentrations.

Our study has shown that H. pylori-positive DU disease has significantly higher fasting serum gastrin concentrations (108.3±35.0 and 85.4±35.1 pg/ml) than those (55.1±17.6 pg/ml) of H. pylori-negative patients. Similar results have been reported by several investigaters^3,5–10). In patients with GU, serum gastrin concentrations were also significantly higher in H. pylori-positive subjects (129.3±47.0 pg/ml in the first group and 99.5±45.3 pg/ml in the second group) than H. pylori-negative patients (69.8±38.0 pg/ml). This is the first report regarding the relation between antral H. pylori infections and serum gastrin levels in patients with GU infected by H. pylori.

This study also showed that eradication of H. pylori infection was accompanied by a significant fall in the serum gastrin concentrations in both GU and DU patients. In contrast, serum gastrin concentrations have increased in patients showing continuously positive for H. pylori and has not changed in those negative for H. pylori infection in both the beginning and the end of study. Our results are similar to those of previous reports^{3,5,6,7,9,10)}.

The mechanism of the hypergastrinemia in DU patients with H. pylori infection is unclear. It has been proposed that the increased serum gastrin concentrations are caused by the organisms ammonia production raising antral surface pH⁷⁾. This would prevent the physiologic suppression of gastrin release by intragastric acid, resulting in inappropriate release of the hormone.

However, Chittajallu RS, et al.^6,9) and Nujumi AME, et al.¹⁰⁾ have demonstrated that median basal gastrin concentration remained unchanged despite either the threefold increase in ammonia production by intragastric infusion of urea, or the complete suppression of bacterial urease activity with acetohydroxamic acid. On the basis of these observations, they have concluded that H. pylori-associated hypergastrinemia is not related to the organisms urease activity and ammonia production.

A second possible mechanism, by which H. pylori infection of the gastric antrum may be stimulating excessive gastrin release, is the effects of antral gastritis. Eradication of the infection results in resolution of the antral gastritis and it is possible that it is the inflammatory cell infiltrate in the region of the G cells that is responsible for hypergastrinemia. Wyatt JI, et al.¹⁶⁾ have demonstrated that hypergastrinemia correlates better with antral gastritis than with H. pylori status.

A third explanation for hypergastrinemia is that it is a compensatory response to inhibition of parietal cell function by H. pylori. Cave DR, et al.¹⁷⁾ have found that the organism has been shown to inhibit parietal cells in vitro and Graham DY, et al.⁸⁾ have demonstrated that acute H. pylori infection may result in profound hypochlorhydria in humans. Some inhibition of parietal cell function may persist during chronic infection of H. pylori, producing a compensatory increase in gastrin release.

Recently, it has been reported that the gastrin-releasing-peptide (GRP), one of non-luminal stimulants of gastrin, might be responsible for hypergastrinemia in patients with DU infected by H. pylori¹⁹⁾.

On the basis of our observations, we have confirmed that chronic antral H. pylori infection causes increased release of serum gastrin, and eradication of the organism results in significant lowering of serum gastrin concentrations in patients with DU. Similar results were also found in patients with GU.

We are further investigating the possible causes that might be responsible for the H. pylori-induced hypergastrinemaia by evaluating changes of antral histologies and by measuring the antral G- and D-cell populations before and after eradication of the organism in peptic ulcer patients.