J. Defize

Effect of Oral Omeprazole on Serum Gastrin and Serum Pepsinogen I Levels

Fasting and meal-stimulated serum gastrin and serum pepsinogen I levels were determined in 8 healthy volunteers before, during, and after administration of 30 mg of omeprazole daily for 14 days. Fasting levels and the integrated increment of serum gastrin were significantly increased after 7 and 14 days of treatment with omeprazole, but not after a single dose. Fasting levels measured 2, 4, 7, 14, and 21 days after stopping treatment with omeprazole and the integrated increment of serum gastrin determined 7 and 14 days after discontinuation of omeprazole were not significantly different from pretreatment levels. Fasting serum pepsinogen I levels increased progressively during omeprazole treatment. This increase was significant after 7 and 14 days of treatment and 2 and 4 days after discontinuing omeprazole. These levels were not significantly different from pretreatment levels 7, 14, and 21 days after omeprazole treatment. Serum pepsinogen I did not significantly change after the test meal. It is concluded that fasting and meal-stimulated serum gastrin levels and fasting serum pepsinogen I levels increase significantly during treatment with 30 mg of omeprazole daily for 14 days, but after stopping treatment there is a rapid return to pretreatment levels.

Clinical significance of pepsinogen A isozymogens, serum pepsinogen A and C levels, and serum gastrin levels

Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (<25 μg/l), a low serum pepsinogen A/pepsinogen C ration (<1.5), and a high serum gastrin level (> 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ration less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes. Cancer 59:952‐958, 1987.

Effect of single and repeated doses of oral omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels

The effect of omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels was studied in 12 healthy volunteers. Omeprazole, 40 mg enteric-coated granules, or placebo was given once daily for nine days in a double-blind crossover study design. Twenty-four hours after a single dose of omeprazole, mean basal and mean pentagastrin-stimulated acid output decreased significantly. This effect was more pronounced after nine days of treatment. Basal pepsin output was significantly reduced only in those subjects with basal anacidity during omeprazole treatment. Stimulated pepsin output was slightly reduced after a single dose but unaltered after nine days of omeprazole. Fasting serum gastrin and serum pepsinogen I levels increased significantly during omeprazole treatment. It is concluded that omeprazole is a potent and selective inhibitor of gastric acid secretion, probably without a direct effect on pepsin secretion. However, in cases of basal anacidity during omeprazole administration, basal pepsin secretion is reduced. During omeprazole treatment, fasting serum levels of gastrin and pepsinogen I rise.

Gastric proteases in Barrett's esophagus

Precursors of the gastric proteases pepsinogen A (pepsinogen I) and pepsinogen C (pepsinogen II) and slow-moving protease were demonstrated in biopsy specimens from Barretts epithelium in 21 of 22 patients with Barretts esophagus; in 14 of them, in variable combinations at different sites. In 13 of 19 patients (68.4%) with detectable pepsinogen A, different isozymogen patterns were found between the Barretts epithelium and the gastric corpus mucosa. Discrepancies consisted mainly of a stronger pepsinogen 5 band in the Barretts epithelium, with a higher incidence in biopsy specimens with features of dysplasia than with no or indefinite dysplasia; the difference was, however, not statistically significant. Zymograms of 69 biopsy specimens from Barretts epithelium were correlated with the histologic type: pepsinogen A and C were most frequently found in the fundic type, least often in the specialized intestinal type. In control gastric corpus biopsy specimens, pepsinogen A and C as well as slow-moving protease were always detectable. The observed variability of gastric protease patterns, in particular of pepsinogen A isozymograms, may be due to differences in expression within the pepsinogen A cluster, suggesting a deregulation of gene expression or partial deletion of the pepsinogen A gene cluster.

Pepsinogen synthesis in monolayer culture of human and rabbit gastric mucosal cells.

SummaryWe have established monolayer cultures of human and rabbit gastric mucosal cells and of isolated rabbit gastric chief cells. These cultures were capable of de novo pepsinogen synthesis and secretion, demonstrated by electrophoresis and subsequent autoradiography of cell lysates and growth medium after culture in the presence of14C-labelled amino acids. Cultures could be maintained for 1 week without overgrowth by fibroblasts.

Pepsinogen A polymorphism in gastric mucosa and urine, with special reference to patients with gastric cancer

Electrophoretic pepsinogen A patterns were determined in gastric fundic mucosa biopsies from 601 patients with various gastric disorders and 25 healthy volunteers. Pepsinogen A patterns with an intense fraction 5 appeared to be associated with gastric cancer and premalignant changes of the stomach (p < 10‐9). In 60 individuals pepsinogen A patterns were determined in normal mucosa from different parts of the stomach. No differences were found between these patterns. In 29 out of 59 gastric cancer patients pepsinogen A could be demonstrated in the macroscopically malignant tissue. In two cases a different pattern compared with uninvolved fundic mucosa was observed.

The influence of omeprazole on the synthesis and secretion of pepsinogen in isolated rabbit gastric glands

Regulation mechanisms of pepsinogen (EC 3.4.23.) synthesis and secretion were studied by following newly synthesized [14C]-labeled pepsinogen during culture of isolated rabbit gastric glands. Omeprazole, a substituted benzimidazole, while almost completely abolishing acid production at 10(-4) M, strongly stimulated secretion of preformed and newly synthesized pepsinogen. Although the pepsinogen synthesis at this concentration of omeprazole was reduced to about 55% of the control rate, a two-fold absolute increase of total secreted pepsinogen was found. This increase was not due to a non specific leakage through disruption of chief cell membranes, as no increase of lactate dehydrogenase in the culture medium could be demonstrated. The stimulated secretion was influenced neither by 10(-3) M cimetidine, 10(-3) sodium thiocyanate nor 10(-4) M atropine. No additivity was found between the carbachol (10(-4) M) or dibutyryl cyclic AMP (10(-3) M) and the omeprazole induced pepsinogen secretion.

Discrepancies between gastric mucosal and urinary pepsinogen A patterns andin vitro synthesis and secretion of human pepsinogen

The relationship between electrophoretic pepsinogen A (PGA) patterns from urine and gastric mucosa was studied in healthy volunteers and in patients with various gastric disorders. Discrepancies between urinary and gastric PGA patterns were found in 63.3% of the individuals. In 9% of the subjects with these discrepancies, the phenotype class in urine was different from that in gastric mucosa. The differences were found in all diagnostic groups. The highest frequency of differences was found in patients with gastric ulcer. The differences were not related to the serum PGA level. More than 80% of the differences were caused by a lower relative intensity of pepsinogen A fraction 5 (Pg5) in urine than in gastric mucosa. The possible origin of differences in PGA isozymogen patterns was studied by organ culture of gastric biopsies. In vitro synthesis and secretion of pepsinogens were studied by electrophoresis and autoradiography. The synthesis rate of PGA in biopsies of 1–2 mm diameter was 40–100 ng/hr. Posttranslational modification of PGA isozymogens was demonstrated. Pg2 and part of Pg4 probably are secondary products of Pg3 and Pg5, respectively. In some individuals the secretion rate ofPg3 was low compared to the other isozymogens. The conversion of Pg3 into Pg2 and the differential secretion of the isozymogens may explain some of the discrepancies between gastric and urinary PGA patterns.

Human pepsinogens: A review of clinical and genetic aspects

In recent years clinical interest in the study of the proteolytic enzymes of the stomach has greatly increased. Human pepsinogens belong to the group of aspartic proteases and are categorized into two main groups: Pepsinogen A (PGA = PG I) and Pepsinogen C (PGC = PG II). Genetic models have been proposed to explain the inheritance of PGA, and a recent multigene model may be of value. PGA phenotypes in urine and gastric mucosa have been determined in healthy volunteers as well as in patients with different gastric disorders. An increased frequency of the ‘intense Pg5’ phenotype seems to be associated with gastric cancer and pre‐malignant conditions, such as atrophic gastritis. Reliable radio‐immunoassay and enzyme‐linked immunosorbent assay techniques have facilitated the study of serum levels of PGA and PGC in different patient groups; in particular, duodenal ulcer patients (high PGA levels) and patients with atrophic gastritis and/or gastric cancer (low PGA levels). The ratio serum PGA/PGC may be introduced for clinical application, being the most convenient non‐invasive marker for the detection of fundic atrophy. While the chromosome localization of pepsinogen has been established, further research is likely to concentrate on the structure and organization of the pepsinogen genes at the DNA‐level, as well as on the development of new isozyme specific monoclonal antibodies.

THIRD NORDIC CONFERENCE Pepsinogen and gastric cancer

Gastric cancer is a heterogenous histologic and etiologic disease entity, making epidemiological and genetic interpretations difficult. According to a histological classification system of Lauren ( I 965), gastric cancer can be divided into two main groups: diffuse type and intestinal type. A considerable fraction of patients present an undifferentiated type. Family and population studies suggest that the diffuse type of gastric cancer is associated with genetic factors. The association with blood group A and the increased relative risk in first degree relatives are confined to this type of cancer (Correa et al. 1973, Lehtola 1978). The significance of the Lewis system in gastric cancer needs further studies (Koprowski et al. 1982). In search of additional subclinical markers for gastric cancer aiding in early diagnosis and identification of high risk groups, we have investigated the significance of qualitative and quantitative