The concentration of pepsinogen I (PG I) in serum is raised in both gastric (GU) and duodenal ulcer (DU) patients^1–6) and correlates positively with the relapse rates of DU⁷⁾. Helicobacter pylori (H. pylori) infection of the gastric antrum is now regarded as one of the important pathogenetic factors for developing the peptic ulcer diseases, and eradication of the infection markedly lowers the ulcer relapse rate.

Recently, it has been suggested that, in humans and animals, serum PG I secretion rates increase with age as does the prevalence of H. pylori infection^8–11). However, there is no consensus on how the mechanism interact with H. pylori infection and hyperpepsinogenemia. Oderada et. al¹²⁾, reported that eradication of H. pylori infection in children with various gastrointestinal disorders results in 25% reduction in the serum PG I concentration. It has become apparent that many of secretory abnormalities in DU, such as hypersecretion of acid, pepsin and gastrin, are to a large extent secondary to H. pylori infection and its associated gastritis^6,13). The chronic inflammation of the gastric antral mucosa induced by H. pylori might increase leakage of the zymogen into the circulation. In addition, H. pylori infection raises the plasma gastrin concentration2–4,12,14–16 and the trophic action of this hormone may increase the chief cell mass and thereby the PG I synthesis.

We have examined the influence of H. pylori infection on serum PG I concentration in patients with peptic ulcer. In addition, we have investigated the extent of any changes of serum PG I concentration after eradication of H. pylori.

Result were expressed as the Means±SD. Student’s t-test was used to determine the significance of difference between means, with differences giving a p value less than 0.001 being considered significant.

All of 736 patients studied, who had either GU or DU, were effectively treated with ranitidine and antacid for 4- to 6-week treatment without any significant side reactions and active ulcer craters were completely healed in all patients on the follow-up endoscopy. After 4-week treatment with metronidazole and TDB, none of the first group patients, who were infected by H. pylori initially, had antral H. pylori both in microscopic and histologic examination of repeated biopsy specimens (Table 4 & 5). However all the second group patients, who were also H. pylori positive at the beginning of the study, and were given only ranitidine and antacid, were still infected by the organism on repeated examination even though ulcers were completely healed (Table 4 & 5). These data suggest that H2-receptor antagonist and antacid do not have any antibacterial action against H. pylori and the 4-week combination therapy of metronidazole and TDB is highly effective for eradication of H. pylori from the antrum. Among the third group patients, initially free of H. pylori infection, none was infected by the organism during the study (Table 4 & 5). Patients infected by H. pylori (511 patients ; GU 208, DU 303) had significantly higher fasting serum PG I concentrations than patients negative for the organism (225 patients: GU 110, DU 115)(range 59.5–298.0 mean 124.3±46.9 ng/ml vs range 21.9–128.8 mean 77.9±25.8 ng/ml, respectively). (p<0.0001)(Table 2 & Fig. 1). The difference in serum PG I concentrations according to the location of ulcer crater was also evaluated. H. pylori positive patients, either GU or DU, had significantly higher PG I levels in serum compared to H. pylori negative patients. (p<0.0001, respectively) (Table 3). In cases of non-infected patients, serum PG I level of GU patients was significantly lower than DU patients (72.4 ± 25.7 vs 83.2 ± 24.9 ng/ml). (p<0.0001)(Table 3). In contrast, the difference between H. pylori-positive GU and H. pylori-positive DU was not significant (125.3 ± 50.6 vs 123.7±44.2 ng/ml(p>0.5) (Table 3). In the 110 patients with successful eradication of H. pylori, there was a significant fall in the fasting serum PG I concentration from 129.8±43.0 ng/ml to 82.4 ±24.0 ng/ml after treatment (p<0.001)(Table 5. Fig. 2). In contrast, fasting serum PG I concentrations of the second group patients whose H. pylori infections were not eradicated were increased even though the difference was not statistically significant (pre-treatment value, 120.8±40.9 ng/ml and post-treatment value: 126.3±40.4 ng/ml)(p>0.5) (Table 5, Fig. 3). In the third group of H. pylori negative 54 patients, there was no change in the fasting serum PG I concentration after the healing of ulcers, with pre-treatment value being 75.1 ±28.0 mg/ml and post-treatment value being 77.3±24.5 ng/ml (p>0.1)(Table 5, Fig. 4).

It is well known that a high serum pepsinogen level is both a feature of established duodenal ulcer and a risk factor for developing duodenal ulcer. In addition, it is also true that in some families with a prominent history of duodenal ulcer an elevated serum PG I level is inherited as an autosomal dominant trait and is a subclinical marker of susceptibility for developing duodenal ulcer disease. Increased serum PG I is also present in patients with gastric ulcer, but there has been no evidence that hyperpepsinogenemia is a risk factor of gastric ulcer disease^1–6). Evidences have been accumulated that various gastric secretory abnormalities associated with peptic ulcer disease are to a large extent secondary to H. pylori infection and its associated gastritis. Even more interesting is the finding that somatostatin deficiency of the gastric mucosa induced by H. pylori infection appears to play an important pathogenetic role in hypersecretion of gastrin and acid in DU patients^17,20). Before evaluating effects of H. pylori infection on the change of serum PG I concentration, we have examined any possible influences of 4- to 6-week treatment of H2-receptor antagonist (ranitidine) and antacid (mylanta) on serum PG I levels. Patients were completely tolerant of the therapy and there were no side effects. There was no change in fasting serum PG I concentrations between the pre-treatment and the post-treatment period (75.1 ± 28.0 ng/ml vs 77.3 ± 24.5 ng/ml). These observations suggests that short-term treatment with either H2-receptor antagonist or antacid does not have an influence on serum PG I concentrations.

In this report, we found that serum PG I was significantly elevated in patients with peptic ulcer diseases with H. pylori infection compared with those without H. pylori infection. This observation is consistent with previous reports on PG I elevations in patients with peptic ulcer^{1–9,11,17–21)}. Interestingly, when comparing the difference of fasting serum PG I levels according to the status of H. pylori infection and the location of ulcer crater, the rate of increment was significantly higher in GU patients than in DU patients (73.1% in GU patients vs 48.7% in DU patients) (Table 3). This study also showed that eradication of H. pylori infection was accompanied by a significant fall in the serum PG I concentrations in both GU and DU patients. In contrast, serum PG I concentrations have increased in patients showing continuously positive for H. pylori and have not been changed in those patients without H. pylori infection in both the beginning and the end of study. Our results are similar to those of previous reports^13,15,22,23). Therefore, our observations that reversible hyperpepsinogenemia I strongly suggests that the increased circulating PG I levels in both GU and DU subjects must be resulted from this bacterial infection. The mechanism of the increased circulating levels of the PG I in peptic ulcer patients with H. pylori infection is still unclear. The effect of acid inhibiting therapy could be responsible for the change in serum PG I concentration after eradication of H. pylori infection. Jansen et al.²⁴⁾ and Biemond et al.²⁵⁾ reported that serum PG I level was reversibly increased during the administration of omeprazole. This possibility, however, is excluded by our findings that, while in the subjects of our study who were treated with only H2 blocking drug and antacid, there were no falls in PG I concentratins. Chittajallu et al.²⁶⁾ suggested that the increased serum PG I concentration could be the end result of H. pylori-induced gastritis. Their hypothesis is that the H. pylori-associated gastritis usually involves the body of the stomach to a significant extent and could result in damage to the chief cells and the mucous neck cell, rusulting in leakage of zymogen into the circulation. And it is also possible that the gastritis increases the permeability of the gastric epithelial surface, enabling back-diffusion of PG I before converting pepsin by the gastric acid.

Studies have shown that the serum PG I concentration correlates with the chief cell mass, basal pepsin output and pentagastrin-stimulated gastric acid and pepsin output. And, it has been confirmed that chronic infection of gastric mucosa with H. pylori can also induce significant increase of serum gastrin concentration^{9,12,14,16,26)}. Considering these findings, it is possible that the hypergastrinemia induced by H. pylori exerts a trophic effect on the pepsinogen-producing cells with resulting hyperpepsinogenemia I.

On the basis of our observations, we have confirmed that chronic antral H. pylori infection causes increased release of serum PG I and eradication of the organism results in significant lowering of serum PG I concentrations in patients with peptic ulcer diseases.

We are further investigating the possible causes that might be responsible for the H. pylori-induced hyperpepsinogenemia I by evaluating histologic changes of the gastric chief cells and mucous neck cells along with the degree of inflammation of the gastric mucosa.