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BACKGROUND & AIMS: Although epidermal growth factor (EGF) inhibits gastric acid secretion, the effects it exerts on gastric chief cells are unknown. The aim of this study was to investigate whether EGF modulates pepsinogen release and intracellular Ca2+ concentrations ([Ca2+]i) and whether the effect involves mitogen-activated protein (MAP) kinase, eicosanoid generation, and nitric oxide. METHODS: Chief cells were obtained by sequential digestion with collagenase and Ca2+ chelation. [Ca2+]i was measured in cells loaded with Fura-2 and NO generation by the NO coproduct citrulline. RESULTS: In situ hybridization, immunohistochemistry, and immunoblotting showed that EGF receptor and MAP kinases were constitutively expressed in chief cells. EGF caused a concentration-dependent stimulation of pepsinogen secretion and MAP kinase activity and determined a 2.5-7.0-fold increase in [Ca2+]i, inositol 1,4,5-tryphosphate, prostaglandin E2, and leukotriene B4. Tyrosine kinase inhibitors and cyclooxygenase and lipoxygenase inhibitors reduced pepsinogen secretion and eicosanoid generation induced by EGF. EGF increased citrulline generation and guanosine 3',5'-cyclic monophosphate accumulation sixfold; the effect was blocked by NG monomethyl-L-arginine, which is an NO synthase inhibitor. CONCLUSIONS: EGF stimulates pepsinogen secretion by activating eicosanoid generation, tyrosine kinases, MAP kinases, Ca2+, NO, and guanosine 3',5'-cyclic monophosphate. (Gastroenterology 1996 Oct;111(4):945-58)

Epidemiological and experimental evidence have shown that nicotine has harmful effects on the gastric mucosa. The mechanisms by which cigarette smoking or nicotine adversely affect the gastric mucosa have not been fully elucidated. In this report, clinical and experimental data are reviewed. The effects of nicotine from smoking on gastric aggressive or defensive factors are discussed. Nicotine potentiates gastric aggressive factors and attenuates defensive factors; it also increases acid and pepsin secretions, gastric motility, duodenogastric reflux of bile salts, the risk of Helicobacter pylori infection, levels of free radicals, and platelet-activating factor, endothelin generation, and vasopressin secretion. Additionally, nicotine impairs the therapeutic effect of H 2 -receptor antagonists and decreases prostaglandin synthesis, gastric mucosal blood flow, mucus secretion, and epidermal growth factor secretion. Although many of the studies provide conflicting results, the bulk of the evidence supports the hypothesis that nicotine is harmful to the gastric mucosa.

The presence of autoimmune gastritis was investigated in 54 women with postpartum thyroiditis. Parietal cell antibodies (PCA) specific against H+, K(+)-adenosine triphosphatase (EC 3.6.1.36) were found in 18 women during pregnancy; in 10 of them, a 2-9-fold increase in the PCA level was observed in the postpartum period. At a 5-year follow-up, the initially PCA-positive women still had elevated antibody levels. Hypergastrinemia and low pepsinogen levels were noted in 4 women. In 2 of these women low serum vitamin B12 levels had developed. In 6 of 9 PCA-positive women examined by gastroscopy, biopsy specimens from the gastric body mucosa contained mononuclear cells, mainly T lymphocytes (CD3+) and macrophages (Leu-M3+) combined with an aberrant epithelial expression of HLA-DR. In four patients with chronic gastritis, all parietal cells, as defined by a specific monoclonal antibody, were found to have immunoglobulin G (IgG) deposits by a double-immunostaining method. Three of them had microscopic evidence of atrophy, whereas in 1 patient the body mucosa was intact. In 1 further patient with intact glands at histological examination, the basolateral membrane of some oxyntic glands was coated with IgG. The selective in situ deposition of antibodies associated with histologically intact parietal cells may support the concept that specific autoantibodies participate in the early pathogenesis of parietal cell destruction.

Dog gastric lipase (DGL) secretion is stimulated in vivo by urecholine, pentagastrin, histamine, 16,16-dimethyl prostaglandin E2, and secretin. Under fasting conditions, DGL is irreversibly inactivated by gastric acid below pH 1.5; consequently, DGL output can be underestimated. This problem has been resolved by buffering the acid or by using an antisecretory drug such as omeprazole during stimulation. There is a clear parallelism between the secretion of DGL and of gastric mucus. This observation led to the present investigation of the cellular localization of DGL using immunofluorescence techniques. Results showed that DGL is cytolocalized in mucous pit cells of gastric glands. Pepsinogen is found in chief cells. To the authors' knowledge, this is the first description of an enzyme (gastric lipase) secreted by mucous-type gastric cells. In contrast to other species, gastric lipase of the dog is located in cardiac, fundic, and antral mucosae.

A seroepidemiologic study of the prevalence of Helicobacter pylori infection in Japan was performed, and the relationship between serum pepsinogen I and II levels (markers of gastritis and gastric atrophy) and H. pylori infection was investigated. Four hundred and eighteen asymptomatic children and adults were studied. The prevalence of anti-H. pylori immunoglobulin G antibody increased with age. For persons born after 1950, the frequency of H. pylori infection increased at approximately 1% per year; for those born before 1950 the prevalence was high (70%-80%) and relatively constant. Serum pepsinogen I and II levels were significantly higher in H. pylori-infected volunteers than in H. pylori-uninfected volunteers [51.6 +/- 3 vs. 42.9 +/- 2 ng/mL (P less than 0.05) for pepsinogen I; 16.0 +/- 1 vs. 7.5 +/- 0.8 ng/mL (P less than 0.001) for pepsinogen II]. The ratio of pepsinogen I to pepsinogen II was significantly lower in H. pylori-infected volunteers (3.5 +/- 0.2) than in uninfected volunteers (6.3 +/- 0.3; P less than 0.001). The apparent decrease in prevalence of H. pylori accompanying the Westernization of Japan may eventually be accompanied by a reduction in the frequency of atrophic gastritis, the precursor lesion of the epidemic form of gastric carcinoma, and ultimately result in a decrease in the incidence of gastric carcinoma in Japan.

The effects of age on basal, meal-stimulated, and human gastrin-17-stimulated gastric acid secretion rates and serum pepsinogen concentrations were evaluated in 41 healthy men and women. Older subjects (ages 44-71 years; mean, 57 years) had higher mean basal, meal-stimulated, and gastrin-17-stimulated acid secretory rates and basal serum pepsinogen I and II concentrations than younger subjects (ages 23-42 years; mean, 33 years). Age-related differences in acid secretion were especially prominent in men, and age-related differences in serum pepsinogen I and II concentrations were more prominent in women. Higher gastric acid secretion rates in older subjects could not be explained by body size (height, weight, body surface area, or fat-free body mass) or by the higher incidence of infection with Helicobacter pylori. Using a multivariate linear regression model, age had an independent positive effect on acid secretion, and H. pylori infection had an independent negative effect. It was concluded that aging is associated with an increase in gastric acid secretion in humans, especially in men, while infection with H. pylori is associated with lower acid secretion rates.

The pepsinogen A isozymogen pattern in gastric mucosa is genetically determined and can be visualized in nondenaturating polyacrylamide gel electrophoresis of supernatants of sonified gastric mucosal biopsies by demonstrating proteolytic activity after converting pepsinogen into pepsin by acid. Pepsinogen isozymogens are present in very low concentrations in the blood but can now be demonstrated in serum by a newly developed immunoblotting procedure. This study investigated whether the serum pepsinogen A isozymogen pattern adequately reflects the pepsinogen A phenotype. Serum and gastric mucosal pepsinogen A isozymogen patterns were compared in 72 subjects from the routine endoscopy program. A close correlation was found between the relative intensities of the pepsinogen A isozymogens in the serum and the gastric mucosal patterns. Increasing the pepsinogen A release into the circulation by oral omeprazole did not affect the pepsinogen A patterns in the blood. It is concluded that the serum pepsinogen A pattern reflects the pepsinogen A phenotype in humans. In addition, no preferential release of a pepsinogen A isozymogen into the circulation was observed. Thus, immunoblotting of serum provides a new and reliable tool to study pepsinogen genetics in humans. Because a relationship was previously shown between specific pepsinogen A phenotypes and gastric malignancies in humans, serum pepsinogen A patterns may provide a tool to detect subjects who are at risk of gastric cancers.

Background/Aims: Leukotrienes (LTs) are involved in many inflammatory conditions including gastric damage induced by nonsteroidal anti-inflammatory drugs. Although LTs stimulate acid secretion, the effect they exert on pepsinogen secretion is unknown. The aim of this study was to investigate whether LTs stimulate pepsinogen secretion by isolated chief cells and to identify the intracellular messengers that mediate this action. Methods: Isolated chief cells were incubated with concentrations of LTB 4 , LTC 4 , LTD 4 , or LTE 4 ranging from 0.1 pmol/L to 10 μmol/L, and pepsinogen release, intracellular calcium and inositol(1,4,5)-trisphosphate (IP 3 ) concentrations were measured. Nitric oxide generation was determined by the amount of citrulline generated during incubation. Results: All four LTs caused a concentration-dependent stimulation of pepsinogen secretion with 50% effective concentration of 0.05-0.1 nmol/L and a dose-dependent increase in cytoplasmic free calcium and IP 3 concentration. The LTB 4 and LTD 4 antagonists caused selective, concentration-dependent inhibition of LTB 4 - and LTD 4 -induced pepsinogen secretion, calcium mobilization, and IP 3 generation. All four LTs increased NO generation, and the effect was inhibited by LTB 4 and LTD 4 antagonists and an NO synthase inhibitor N G -monomethyl-l-arginine and reversed by l-arginine. N G -monomethyl-l-arginine caused a 50%–60% reduction of LT-induced pepsinogen release. Each of the four LTs caused a fivefold increase in 5′-cyclic guanosine monophosphate. Conclusions: LTs are powerful stimulators of pepsinogen secretion in isolated chief cells and act via occupancy of specific cell-surface receptors.

Low serum levels of pepsinogen A are indicative of chronic atrophy, a risk factor for gastric cancer. This study investigated the relationships between low pepsinogen A levels, Helicobacter pylori seropositivity, and gastric cancer rates in 17 populations worldwide.In each center, about 200 randomly selected subjects (50 male and 50 female, aged 25-34 and 55-64 years) provided serum samples for pepsinogen analysis and H. pylori serology.Cumulative gastric cancer rates were associated with the prevalence of low pepsinogen A levels in men (coefficient, 0.15 [P = 0.06] for mortality; coefficient, 0.36 [P = 0.01] for incidence) but not women. The prevalence of low pepsinogen A levels was also correlated with H. pylori seropositivity in the older age group (r = 0.55; P = 0.02). Low pepsinogen A levels were significantly more common in the older group (7.5% vs. 2.1% in the younger group; P0.001), among women (5.5% vs. 4.1% in men; P = 0.04), and among nonsmokers (5.8% vs. 2.9% in current smokers; P = 0.001).Low pepsinogen A levels are more common in areas with a high seroprevalence of H. pylori and in men in areas with high rates of gastric cancer. The prevalence of low pepsinogen A levels increases with age, but the excess in women and nonsmokers could reflect factors other than gastric pathology.

Background: Motilin and erythromycin bind the same receptor in the gastrointestinal muscle cells. Motilin stimulates pepsinogen secretion in humans and dogs. However, it is unclear whether it acts directly on gastric chief cells or via other neurotransmitters. Methods: Isolated gastric chief cells were obtained from guinea pig stomach by collagenase digestion and calcium chelation with ethylene glycol-bis(B-amynomethyl ether)- N , N , N ′, N ′-tetraacetic acid. Results: Significant stimulation of pespinogen secretion induced by motilin occurred at 1 pmol/L, half maximum at 10 pmol/L, and maximum at 100 pmol/L. Erythromycin caused significant stimulation at 1 pmol/L, half maximum at 100 pmol/L, and maximum at 1 nmol/L. Atropine (1 μmol/L) had no effect on either motilin- or erythromycin-induced pepsinogen secretion. Motilin and erythromycin determined a threefold increase in the intracellular calcium concentrations. Pretreatment of isolated chief cells with motilin and erythromycin induced a reversible, dose- and time-dependent desensitization of the pepsinogen secretion stimulated by carbachol and cholecystokinin but not that stimulated by secretin, vasoactive intestinal peptide, or prostaglandin E 2 . Conclusions: Motilin and erythromycin directly stimulate pepsinogen secretion in isolated chief cells.

Elucidation of receptors and mediators regulating gastric pepsinogen secretion has lagged behind understanding of the factors that control acid secretion. During the past decade, as a consequence of the development of in vitro models for studying the control of pepsinogen secretion at the cellular level, much information about chief cell receptors and signal-transduction mechanisms has been obtained, including the identification and characterization of receptors for secretin, vasoactive intestinal polypeptide, cholinergic agonists, gastrin, cholecystokinin, peptide YY, and cholera toxin. Moreover, these cell preparations have permitted secretagogue-induced changes in chief-cell calcium concentration, protein kinase C distribution, and phosphoinositide and cyclic nucleotide content to be measured and related to changes in pepsinogen secretion. This article reviews these advances, discusses areas of uncertainty and controversy, and indicates areas for future investigation.

To better understand the mechanism by which ethanol causes gastric mucosal injury, the effects of ethanol on isolated guinea pig gastric chief cells were investigated in vitro. Ethanol at 300–900 mmol/L dose-dependently stimulated an increase in pepsinogen release without affecting chief cells' viability. Ethanol stimulated an increase in initial Ca2+ influx rate and intracellular Ca2+ concentration at the same concentrations as it stimulated pepsinogen release, whereas it did not stimulate cyclic adenosine monophosphate accumulation. Pepsinogen release stimulated by 900 mmol/L ethanol was almost equal to that stimulated by 10−8 mol/L COOH terminal octapeptide of cholecystokinin. Ethanol did not stimulate an increase in the accumulation of inositol trisphosphates and tetrakisphosphates in [3H]inositol-labeled chief cells, whereas cholecystokinin octapeptide caused a significant increase in inositol trisphosphates and tetrakisphosphates. Ethanol-stimulated pepsinogen release and increases in the initial Ca2+ influx rate and intracellular Ca2+ concentration were inhibited by 0.5 mmol/L La3+ or 1 mmol/L ethylene glycol tetraacetic acid but were not inhibited by nifedipine or verapamil. These results suggest that the effect of ethanol on pepsinogen release from the gastric chief cells may be due to its opening of a Ca2+ channel that is sensitive to La3+ and that the pepsinogen releasing action of ethanol may be one of factors for ethanol-induced gastric mucosal injury.

Twenty-nine nongastrectomized and three partially gastrectomized patients with chronic reflux esophagitis resistant to 12 weeks' treatment with histamine H2-receptor antagonists were treated with a daily oral dose of 20-40 mg of omeprazole for 12-30 months. Basal serum gastrin, serum pepsinogen A, and serum pepsinogen C concentrations were monitored at regular intervals. Serum gastrin levels significantly (P less than 0.01) increased threefold to fourfold during the first 1-2 months of the study when all patients ingested 40 mg of omeprazole daily. Dose reduction to 20 mg did not significantly decrease gastrin levels. Serum gastrin levels showed a trend to further increase after the first 3 months of treatment, reaching statistically significant differences for values from the 3-12-month period (P less than 0.05) and from the 3-24-month period (P less than 0.005). Women and patients with high basal serum gastrin levels before omeprazole treatment were more likely to achieve higher serum gastrin levels during omeprazole treatment. Serum pepsinogen A and C levels were significantly (P less than 0.01) increased at all time intervals during long-term treatment with omeprazole. No significant tendency toward higher serum pepsinogen C levels in time was observed. However, serum pepsinogen A levels and the ratio of pepsinogen A to pepsinogen C further increased significantly (P less than or equal to 0.05) during the initial 3-12-month period. However, this trend was not observed anymore afterward. Antrectomized patients did not show increases in serum gastrin and serum pepsinogen A and C levels, suggesting that hypergastrinemia may be involved in the observed hyperpepsinogenemia.

Ability to taste phenylthiocarbamide is genetically determined and has been investigated as a possible genetic marker for disease. This study examined phenylthiocarbamide taste sensitivity in gastric and duodenal ulcer disease. The study sample included 164 patients with gastric ulcer, 134 with duodenal ulcer, and 299 community controls. Eight concentrations of phenylthiocarbamide in distilled water were obtained by binary serial dilution. The lowest concentration distinguished by taste from distilled water defined taste threshold. Bimodality of threshold distributions distinguished nontasters from tasters. Comparisons of patients with controls gave odds ratios of nontaste in gastric ulcer and duodenal ulcer of, respectively, 0.7 (P greater than 0.1) and 1.3 (P greater than 0.03). The power of detecting at least a twofold difference between patients and controls in the odds of nontaste was 80%. Nontaste was more common in duodenal than in gastric ulcer patients (odds ratio = 2.0, P = 0.02). Taste sensitivity was unassociated with other genetic factors related to ulcer--ABO blood group, secretor status, and serum pepsinogen 1 level. The difference between gastric and duodenal ulcer patients in the ability to taste phenylthiocarbamide may be genetic; however, this study's inability, despite substantial power, to detect at least a twofold difference between patients and controls suggests that if phenylthiocarbamide taste sensitivity is a genetic factor in peptic ulcer, the relationship is weak.

We have determined the ultrastructural localization of pepsinogen II (PG II) in aldehyde-osmium fixed, resin-embedded ultrathin sections of human gastric fundic and pyloric gland mucosa and duodenum using the protein A immunogold technique and antiserum specific for PG II. Chief cells contained homogeneous, finely granular secretory granules that were uniformly PG II-positive. In contrast, mucous neck, pyloric gland, and Brunner's gland cells contained secretory granules consisting of an eccentrically placed dense core surrounded by a clear matrix; PG II immunoreactivity was concentrated over the dense core of these biphasic granules. Pyloric gland cells also contained monophasic secretory granules having the same electron density, texture, and PG II immunoreactivity as the nucleoids of biphasic granules and clear vesicular granules that were PG II-negative. Vesicular granules also were found in Brunner's gland cells. The Golgi region of pyloric gland cells contained small PG II-positive monophasic granules adjacent to small PG II-negative vesicular granules. This observation suggests that biphasic granules may form in the Golgi region of pyloric gland cells by fusion of PG II-containing monophasic granules and PG II-unreactive vesicular granules.

A new experimental model, the isolated perfused antrectomized pig stomach with intact vagal innervation, was shown to produce pepsinogen and gastric acid upon electrical stimulation of the vagus nerves and by intravascular administration of carbachol (from a basal value of 111 +/- 24 units of pepsin per minute and 0.044 +/- 0.012 mEq H+/min to 393 +/- 75 units of pepsin per minute and 0.102 +/- 0.022 mEq H+/min upon vagal stimulation). Vagal stimulation also increased the release of the neuropeptide gastrin-releasing peptide to the venous effluent from 0.42 +/- 0.12 to 3.1 +/- 0.95 pmol/min. Intravascular infusions of gastrin-releasing peptide at a concentration of 10(-8) mol/L resulted in a threefold increase in pepsinogen secretion and a small increase in acid output. Because gastrin-mediated effects of gastrin-releasing peptide are excluded with this preparation, our results show that gastrin-releasing peptide acts either directly or through another unknown local mediator on the pepsinogen-secreting cells. Gastrin-releasing peptide may thus participate in the vagal control of pepsinogen secretion.

We investigated the possibility that serum pepsinogen I (PG I) and pepsinogen II (PG II) levels might differ as risk factors for duodenal ulcer and gastric ulcer. From 1967 to 1970, serum was obtained from 7498 Japanese men in Hawaii, and the cohort was followed up to 1981 for the development of peptic ulcer disease. Pepsinogen I and PG II levels in stored serum were significantly higher in the subjects who developed duodenal ulcer (n = 43) or gastric ulcer (n = 115) than in 212 control subjects. The linear trend in risk of each type of ulcer was highly significant for both PG I and PG II. An elevated serum PG I level (greater than or equal to 130 micrograms/L), however, was associated with about a threefold higher odds ratio for duodenal ulcer than for gastric ulcer (8.37 vs. 2.83), whereas an elevated PG II level (greater than or equal to 30 micrograms/L) was associated with about a threefold higher odds ratio for gastric ulcer than for duodenal ulcer (18.21 vs. 6.49). In contrast, the PG I/PG II ratio was significantly lower in the gastric ulcer than in the control and duodenal ulcer cases, and showed a significant linear trend in risk only for gastric ulcer. In addition, a PG I/PG II ratio of less than 4.0, which has been shown previously to be indicative of chronic gastritis, was associated with an almost 10-fold higher odds ratio for gastric ulcer than for duodenal ulcer (7.35 vs. 0.79). The results indicate that an elevated serum PG I level is a major risk factor for duodenal ulcer, whereas an elevated serum PG II level and a low PG I/PG II ratio are major risk factors for gastric ulcer.

When maintained in organ culture, rabbit gastric mucosal biopsies incorporated [14tc]leucine into tissue protein and secreted labeled protein into culture medium steadily for 24 hr. Incorporation of radioactivity was abolished by cycloheximide. When examined by sodium dodecyl sulfate gel electrophoresis, dextran gel filtration, and ion exchange chromatography, 65 to 90% of macromolecular radioactivity secreted into culture medium migrated coincidentally with enzymatically assayed pepsinogen. Pepsin activity in cultured biopsies did not decrease during 24 hr of organ culture. Nevertheless, pepsin activity increased linearly in culture medium during this period. Acetylcholine markedly stimulated secretion of labeled protein and pepsinogen by cultured biopsies. In the presence of a subthreshold concentration (10(-10) M) of acetylcholine, pentagastrin, secretin, and the octapeptide of cholecystokinin, all stimulated protein secretion. Over-all incorporation of [14C]leucine into protein by cultured biopsies was stimulated by 10(-9) M pentagastrin. These results directly demonstrate: (1) synthesis and secretion of protein and pepsinogen by isolated gastric mucosa, (2) stimulation of gastric secretion of protein by acetylcholine and polypeptide hormones, and (3) stimulation of gastric synthesis of protein by pentagastrin.

Four cases of Barrett's esophagus are presented. Three cases presented with significant esophageal bleeding and one case presented with high esophageal stricture. Gastrointestinal panendoscopy was done in each case and multiple biopsies were taken. The biopsies were utilized for histomorphology, pepsinogen agar gel electrophoresis, and tissue gastrin assays. Tissue gastrin levels in esophageal mucosa were elevated in 2 cases when compared to controls with and without hiatus hernia. Pepsin and acid secretory studies were done by isolating the esophagus. Barrett's esophagus was shown to produce pepsin by both chemical studies (2 cases) and agar gel electrophoresis at pH 5.7 (3 cases), and was also shown to produce acid. The mucosa contained either cathepsin or cathepsin and pepsinogens in all cases. Nissen's fundoplication was performed in all of the patients. Of 3 patients who were bleeding, 2 who consented for this operation stopped bleeding after the operation. It is to be noted that the usual clinical treatment of antacids, bedrest, and raising the head end of the bed failed in all of the patients. The follow-up of 9 months to 3 years postoperatively has shown persistence of Barrett's mucosa with no evidence for any reversion to normal esophageal type.

Seventeen of 37 healthy volunteers participating in studies of acid secretion and 1 patient with Zollinger-Ellison syndrome became rapidly and profoundly hypochlorhydric. A mild illness with epigastric pain occurred in 9 subjects, usually several days before detection of hypochlorhydria. Gastric mucosal biopsy specimens taken from subjects during hypochlorhydria revealed severe fundal and antral gastritis; however, even when acid secretion was severely depressed, parietal cells were abundant and appeared normal histologically. During hypochlorhydria, gastric permeability to hydrogen, sodium, and lithium was normal in 4 subjects. Serum gastrin concentrations were usually normal, whereas serum pepsinogen concentrations were invariably elevated. Serum parietal cell antibodies were not present. Acid secretion returned to near baseline levels in 14 of 17 subjects after a mean of 126 days (range 53--235); severity of gastritis diminished concurrently in 7 of 10 subjects on whom biopsies were serially performed. An infectious etiology is suspected, although serologic studies and bacterial and conventional viral cultures of stool and gastric juice have not identified a candidate agent.

Pepsinogen I and pepsinogen II were purified from gastric mucosa and used to develop a radioimmunoassay for pepsinogen II and an improved radioimmunoassay for pepsinogen I. Each immunochemically homogeneous preparation contained only its characteristic components by radioelectophoretic analysis, and migrated as a singly band in polyacrylamide gel. The mean (+/- SD) level of serum pepsinogen II in 42 healthy control subjects was 10,8 +/- 3.8 ng/ml, significantly less (p less than 0.001) than the level of pepsinogen I, which was 62.9 +/- 22.2 ng/ml. The correlation between serum pepsinogen I and pepsinogen II was highly significant (r = 0.700, p less than 0.001) in these subjects. In 20 patients with pernicious anemia the mean serum pepsinogen II level was 10.6 +/- 2.5 ng/ml, not different from normal, but significantly higher (p less than 0.001) than the level of pepsinogen I which was 5.9 +/- 4.7 ng/ml. IN 10 patients with total gastrectomy, serum pepsinogen I was 3.9 +/- 3.1 ng/ml and serum pepsinogen II was 3.2 +/- 3.1 ng/ml; both values were significantly lower (p less than 0.001) than the corresponding levels in pernicious anemia. The predominance of pepsinogen I in the serum of healthy control subjects suggests that either the gastric chief cell normally releases more pepsinogen I than pepsinogen II into the circulation or that pepsinogen I has longer metabolic clearance rate than pepsinogen II. The marked decrease in serum pepsinogen I in patients with pernicious anemia is best explained by a loss of gastric chief cells due to severe atropic gastritis of te fundic glands. The normal distribution of serum pepsinogen II levels in these patients may reflect an increased number of pyloric glands due to pyloric gland metaplasia of the proximal stomach.

A significant association has previously been found between a betazole-induced decrease in serum group I pepsinogen (PG I) levels and a low peak acid output (PAO) in symptomatic patients with vagotomy and gastric resection or a drainage procedure. This study compares the effect of betazole on serum PG I levels and gastric acid output in 245 unoperated patients (115 duodenal ulcer, 25 prepyloric ulcer, 32 gastric ulcer, 73 nonulcer) and in 73 symptomatic postoperative patients (15 subtotal gastric resection, 28 vagotomy and gastric resection, 30 vagotomy and drainage). A negative serum PGI response (2-hr serum PG I level less than 92% of basal) occurred in 10 (4.1% of the unoperated patients and in 31 (42.5%) of the postoperative patients. Seven (70%) of the former and 29 (93.5%) of the latter patients had a PAO of less than 10 mEq per hr, indicating that a negative serum PG I response is associated with a low PAO in both unoperated and postoperative patients. The PAO was greater than 10 mEq per hr in 93.1% of the 277 patients with a 2-hr serum PG I level of more than 92% of basal. Additional studies revealed that neither aspiration of gastric juice nor perfusion of the stomach with acid altered the serum PG I response. This suggests that topical acid does not modulate the effect of betazole on serum PG I levels. Finally, a negative serum PG I response has been shown to be paradoxical, in that gastric pepsin levels have been found to increase over basal concurrently with the decrease in serum PG I levels.

Serum group I pepsinogen (PG I) levels, basal acid output, and peak acid output (PAO) have been determined in 120 patients, 54 with duodenal ulcer, 14 with prepyloric ulcer, 12 with gastric ulcer, and 40 without ulcer. The correlation between serum PG I and PAO was statistically significant (r = 0.736, P less than 0.001) up to a serum PG I level of 250 ng per ml. Serum PG I levels above 250 ng per ml were associated with a plateau in the PAO. Each of 8 patients with a serum PG I of less than 40 ng per ml had a PAO of less than 10 mEq per hr. Of 34 patients with a serum PG I over 200 ng per ml, 29 (85.3%) had a PAO of greater than 40 mEq per hr and all had a PAO above 34 mEq per hr. Of 51 patients with a serum PG I between 60 and 150 ng per ml, 47 (92.2%) had a PAO of between 10 and 40 mEq per hr. The results indicate that a significant relationship exists between the concentration of PG I in serum and the acid secretory capacity of the gastric mucosa.

We have examined relationships among the aspartic proteinases in rat and human gastric mucosa by electrophoretic analysis in polyacrylamide gel and by immunoblotting and immunohistochemical staining using rabbit antisera to human pepsinogen I (PG I), pepsinogen II (PG II), and slow-moving proteinase. By electrophoretic analysis, the major proteolytic bands in mucosal extracts from each of three strains of rats had rates of anodal migration that were similar to the fastest migrating isozymogens of human PG I. However, immunoblots revealed that these bands and several minor proteolytic bands with slower rates of anodal migration reacted with antiserum to PG II. Two proteolytic bands in rat gastric mucosa that migrated concurrently with human slow-moving proteinase reacted with antihuman slow-moving proteinase reacted with antihuman slow-moving proteinase. None of the proteolytic bands in rat gastric mucosa reacted with anti-PG I. By immunohistochemical staining, anti-PG I failed to stain any cells in rat fundic gland or antral mucosa. By contrast, anti-PG II stained mucus neck and chief cells in fundic gland mucosa and pyloric gland cells in antral mucosa, and anti-slow-moving proteinase stained surface and foveolar epithelial cells throughout the stomach. The results indicate that the gastric mucosa of the rat does not contain PG I.

The familial aggregation of peptic ulcer disease has been well established, as has its association with such clear-cut genetic factors as blood group O and nonsecretor status. However, the genetics of this disorder, or group of disorders, is still in question. Polygenic inheritance is the prevailing hypothesis that has been proposed for peptic ulcer. This hypothesis was based primarily on the exclusion of a simple mode of inheritance for all ulcer disease. Genetic heterogeneity is an alternative hypothesis that can explain both the familial aggregation of peptic ulcer disease and the lack of a simple Mendelian pattern of inheritance. The evidence for genetic heterogeneity in peptic ulcer disease is reviewed, and studies are proposed to test this hypothesis.

Two immunologic subclasses of human pepsinogen I alpha-PG I and beta-PG I, have been identified based on their reactivity toward a murine monoclonal antibody that recognizes an epitope on the alpha-PG I isozymogens. The antibody was used to purify the major alpha- and beta-isozymogens from gastric mucosa and to determine their contributions to the previously described genetic polymorphism of PG I. The alpha-epitope was localized to the pepsin region of the molecules. The two major alpha-PG I isozymogens (Pg 3 alpha and Pg 5 alpha) and the major beta-PG I isozymogen (Pg 4 beta) were demonstrated to contain net charge differences located in the respective pepsin and activation peptide regions. We propose that the alpha- and beta-subclasses contain net charge amino acid substitutions encoded by the corresponding pepsinogen genes: PGA3, PGA4, and PGA5.

Serum group I pepsinogen (PG I) levels have been determined by radioimmunoassay in 924 subjects. The mean levels in 300 healthy control subjects and in 389 hospitalized controls were 110.6 and 100.0 ng per ml, respectively. The "normal" range is estimated to be between 50 and 175 ng per ml. The mean level of serum PG I in 7 patients with Zollinger-Ellison syndrome was 503.9 ng per ml; values ranged between 315 and 921 ng per ml. The 77 patients with duodenal ulcer had a mean serum PG I level of 221.3 ng per ml; 49 (63.6%) had values greater than 175 ng per ml. The distribution of serum PG I values was bimodal in the patients with duodenal ulcer whereas it was unimodal in both groups of control subjects. Mean serum PG I levels in 13 patients with both duodenal and gastric ulcer and in 18 patients with prepyloric ulcer were, respectively, 177.2 and 179.4 ng per ml. Approximately one-half of these patients had high values. The 28 patients with gastric ulcer had a mean serum PG I level of 116.6 ng per ml; 6 (21.4%) had high values. With the exception of 3 patients with gastric ulcer, none of the 136 patients with peptic ulcer had a low (less than 50 ng per ml) level of serum PG I. In 37 patients with chronic alcoholism the mean level of serum PG I was 73.4 ng per ml. The observed gradient in the mean level of serum PG I among the groups of patients studied is similar to that which has been reported for maximally stimulated gastric acid output. This finding suggests that the secretory potential of the fundic gland mucosa of the stomach may be reflected by the level of PG I in serum.

In vivo observations have suggested that acid secretion may potentiate pepsinogen release. We measured pepsinogen and acid secretion by guinea pig fundic mucosal sheets stimulated by 10(-4) M histamine, 10(-8) and 10(-9) M cholecystokinin, and 3 x 10(-7) M carbamylcholine and then investigated the effects of 10(-4) M omeprazole on basal, carbachol-stimulated, and cholecystokinin-stimulated secretion. Histamine increased basal acid secretion fivefold (p less than 0.01) without altering pepsinogen secretion. Cholecystokinin did not stimulate acid secretion but increased pepsinogen secretion by factors of 23.1 at 10(-8) M and 9.1 at 10(-9) M (both p less than 0.01). The combination of 10(-4) M histamine and 10(-9) M cholecystokinin increased acid secretion 3.5-fold and pepsinogen secretion 6.4-fold, statistically equivalent to the sum of the effects of histamine and cholecystokinin alone. Carbachol increased acid secretion and pepsinogen secretion by factors of 4.0 and 10.9, respectively (both p less than 0.01). Pretreatment with 10(-4) M omeprazole abolished basal and carbachol-stimulated acid secretion. However, pepsinogen secretion was unaffected (p greater than 0.05). Furthermore, omeprazole-treated tissues increased pepsinogen secretion by factors of 10.0 with 3 x 10(-7) M carbachol and 9.1 with 10(-9) M cholecystokinin (both p less than 0.01). Thus, basal and secretagogue-stimulated pepsinogen secretion appear independent of acid secretion in intact guinea pig mucosa.

To characterize bleeding from gastric red spots in patients with cirrhosis, three groups of patients were studied: (a) 11 cirrhotic patients bleeding from gastric red spots, (b) 18 nonbleeding cirrhotic patients without gastric red spots, and (c) 13 noncirrhotic patients with endoscopic normal mucosa (controls). Histologic examination of antral biopsy specimens revealed a diffuse capillary ectasia without inflammation in 8 of the 11 cirrhotic patients with gastric lesions. Morphometric analysis disclosed a significantly greater mean mucosal capillary cross-sectional area in cirrhotic patients with gastric lesions (mean +/- SE, 1371 +/- 320 microns2) than in those without gastric lesions (541 +/- 61 microns2) (p less than 0.005) or controls (353 +/- 20 microns2) (p less than 0.001). Hypergastrinemia was detected in 8 of the 11 cirrhotic patients with lesions, in 2 of the 18 cirrhotic patients without gastric lesions, and in none of the controls (p less than 0.001). Gastrin serum levels correlated significantly (r = 0.80) with mean mucosal capillary cross-sectional area in patients with cirrhosis. Pepsinogen I serum levels below 20 ng/ml were observed in 7 of the 11 cirrhotic patients with lesions, in 1 of the 18 cirrhotic patients without lesions, and in none of the controls. These data indicate that bleeding from gastric red spots in patients with cirrhosis is a distinct entity characterized by vascular ectasia of the gastric mucosa. This condition seems to be associated with hypergastrinemia and low serum levels of pepsinogen I.

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.

From 1 to 5% of patients can be expected to develop recurrent ulceration following current surgical therapy for peptic ulcer disease. The development of recurrent ulcer frequently reflects an inadequacy of the initial procedure. The nature of the inadequacy is often difficult to delineate because of alterations in anatomy and physiology and the lack of accurate diagnostic procedures. Incomplete vagotomy and inadequate gastric resection account for the vast majority of surgical deficiencies. Gastrinoma, retained gastric antrum, and hyperparathyroidism are the most frequently encountered endocrine causes. A thorough evaluation must include gastrointestinal X-rays, fiberoptic endoscopy, multiple serum calcium and gastrin determinations, and provocative testing. Medical management of recurrent ulcer fails in the vast majority of cases. Reoperation is successful in about 70% of cases and has a mortality rate of 4%. Recurrent ulcer after simple gastroenterostomy is best treated by gastric resection or vagotomy and resection. After initial adequate gastric resection, vagotomy alone usually suffices. Antrectomy and, if necessary, re-vagotomy should be done for recurrent ulcer after vagotomy and drainage. Re-vagotomy alone is usually effective therapy for recurrent ulcer after initial vagotomy and resection. Non-acid reducing operations should not be done, as they result in high mortality and high second recurrence rates.

Peptic activity has long been recognized as an essential factor in the pathogenesis of peptic ulcer and related diseases, but only recently has it become clear that. this activity is derived from a remarkable diversity of enzymes, all of which belong to the aspartic proteinase family of enzymes. These include two types of pepsinogens and two types of cathepsins. In recent years, considerable progress has been made in characterizing these proteinases and in applying this information to the study of a number of gastrointestinal disorders. The intent of this article is to update recent basic and clinical information on these topics and to suggest several areas that merit further investigation.

Serum group I pepsinogen (PG I) levels have been determined before and at intervals after the administration of betazole hydrochloride (Histalog) in 50 symptomatic postoperative patients, 20 with and 30 without recurrent ulcer, after either a vagotomy and gastric resection or a drainage procedure. In patients with recurrent ulcer, mean serum PG I levels increased after betazole and reached a maximum of 116.5 +/- 2.2% (SE) of basal at 2 hr; range 98.9 to 135.7%. In contrast, mean serum PG I levels decreased in patients without recurrent ulcer and reached a nadir of 75.0 +/- 4.3% of basal at 2 hr; range 46.9 to 142.4%. All 20 patients with recurrent ulcer and 5 patients without recurrence had a 2-hr serum PG I level of more than 98% of basal, while each of the remaining 25 patients without recurrent ulcer had a 2-hr level of less than 92% of basal. A 2-hr serum PG I level of more than 98% of basal was also correlated with a vagotomy and drainage, a peak acid output of more than 11 mEq per hr, and a positive insulin test, while a level of less than 92% of basal was correlated with a vagotomy and gastric resection, a peak acid output of less than 11 mEq per hr, and a negative insulin test. In addition, basal serum PG I and serum gastrin levels were significantly higher (P less than 0.001) in patients with the former type of PG I response than in those with the latter type of response. The cause of each type of response is not certain, but the data suggest that one of the determinants may be the completeness of vagotomy.

Serum group I pepsinogen (PG I) levels have been determined by radioimmunoassay in 15 patients without, recurrent ulcer after vagotomy and either a gastric resection or a drainage procedure. The mean (+/-SE) levels were 151.8 +/- 16.9 ng per ml in the patients with recurrent ulcer and 79.7 +/- 9.8 ng per ml in those without recurrence (P less than 0.001). A recurrent ulcer was present in 6 of 7 patients with an elevated serum PGI (greater than 175 ng per ml) but not in any of 10 patients with a low serum PGI (less than 50 ng per ml). The correlation between serum PG I and peak acid output (PAO) was statistically significant in patients with recurrent ulcer (pi=0.815, P less than 0.001) and in those without recurrence (r= 0.540, P less than 0.025). In patients with recurrent ulcer, a serum PG I level within the normal range (50 to 175 ng per ml) was uniformly associated with a PAO of more than 10 mEq per hr. In contrast, of 10 patients without recurrent ulcer and a normal serum PG I, eight had a PAO of less than 10 mEq per hr. The reason for the discordant results in the two groups of patients is not certain.

We examined in a controlled study whether psychologic disturbances in men with peptic ulcer disease were related to other potential ulcer "risk factors" (serum pepsinogen concentrations, cigarette smoking, and intake of alcohol, aspirin, or coffee). Psychopathology in general, personality features of hostility, irritability, and hypersensitivity, and impaired coping ability (low ego strength) each correlated significantly with serum pepsinogen concentration in ulcer patients (p less than or equal to 0.005). Cigarette smoking and intake of alcohol and aspirin were increased in ulcer patients but unrelated to psychopathology. Depression was the variable that best discriminated ulcer patients from nonulcer controls; a negative perception of life events, number of relatives with ulcer, and serum pepsinogen I concentration also had a major, unique discriminating value, whereas smoking played a relatively minor role independent of the other variables examined. Our study supports the concept that several interacting factors (psychologic, behavioral, and genetic/physiologic) are likely involved in peptic ulcer disease. Emotional stress may predispose to ulcers by producing gastric hypersecretion, as manifested by hyperpepsinogenemia.

Because it has not been possible to collect gastric lymph by cannulation of lymph vessels, the methods of renal micropuncture were adapted to collection and analysis of 0.5- to 3-mu samples obtained by puncturing lymph vessels on or immediately adjacent to the ventral surface of the dog's stomach. Samples of gastric lymph collected immediately after completion of surgical exposure of the stomach were subjected to acrylamide gel electrophoresis, and they were found to show all the protein bands exhibited by simultaneously collected samples of plasma. Quantitative analysis of similar samples by cellulose acetate electrophoresis gave the following ratios of protein concentration in gastric lymph to plasma: total protein, 0.51; albumin, 0.68; total globulins, 0.42; alpha1-globulin, 0.49; alpha2-globulin, 0.62; beta-globulin, 0.35; fibrinogen, 0.39; and gamma-globulin, 0.46. When samples were collected over 4 hr the concentrations of all proteins in lymph increased, and an argument is presented that this was not the result of increasing small pore size as the result of injury. When the mucosa was irrigated with solutions of dithiothreitol, a substance causing plasma shedding, the concentrations of proteins in gastric lymph over a 4-hr period were similar to those found in control experiments. Gastric lymph mixed with 100 mN HCl was found to have proteolytic activity.

Two brothers with pachydermoperiostosis, an autosomal dominant syndrome characterized by digital clubbing, periosteal new bone formation, coarse facial features with thick, furrowed, and oily skin, presented in their twenties with severe complicated duodenal ulcer disease requiring multiple operations. Their father and one paternal uncle also had pachydermoperiostosis and a past history of ulcer dyspepsia. The mother, one sister, two maternal aunts, and one other paternal uncle were healthy. Both brothers had giant hypertrophic gastritis (Ménétrier's disease). Their pentagastrin-stimulated acid output and fasting and meal-stimulated serum gastrin levels were normal, but their serum pepsinogen I and II levels were markedly elevated. The father had hypochlorhydria and a low serum pepsinogen I/II ratio, suggesting atrophic gastritis. This family study raises the possibility that pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer may be genetically related.

The purpose of these controlled studies was to determine the prevalence of acid-pepsinogen hypersecretion in 173 patients with duodenal ulcer disease [88 Americans (75 men, 13 women) and 85 Chinese (66 men, 19 women)]. One-half to two-thirds of duodenal ulcer patients of either sex had acid hypersecretion or hyperpepsinogenemia, or both. When Chinese and American duodenal ulcer patients were compared, the two ethnic groups had similar serum pepsinogen I and II concentrations and similar maximal acid outputs per kilogram body weight. In contrast, Chinese duodenal ulcer patients had significantly lower basal acid outputs per kilogram body weight than American duodenal ulcer patients. We conclude that acid-pepsinogen hypersecretion is present in the majority of American and oriental duodenal ulcer patients.

Folic acid absorption was studied in 12 elderly subjects with atrophic gastritis and 10 elderly normal controls using tritium-labeled pteroylmonoglutamic acid. Two folic acid absorption tests were carried out on each subject with 120 ml of either water or 0.1 N HCl. Folic acid absorption was significantly lower in subjects with atrophic gastritis than in normal controls (31% vs. 51%, respectively; p less than 0.01). In subjects with atrophic gastritis, folic acid absorption rose significantly to 54% (p less than 0.001) when administered with acid, but did not change in normal controls (50%). Serum folate levels were normal in all subjects. Proximal small intestinal pH was higher in atrophic gastritis subjects than in normal controls (7.1 vs. 6.7, respectively; p less than 0.05), as were bacterial counts of small intestinal fluid (p less than 0.01). Bacteria cultured from the aspirates of subjects with atrophic gastritis were able to synthesize folate in vitro when incubated in a folate-free medium. Atrophic gastritis results in folic acid malabsorption but not in folate deficiency, possibly due to increased bacterial synthesis of folate in the small intestine.

The secretion of pepsinogen and intrinsic factor (IF) in response to various known stimulators and inhibitors of gastric acid secretion was examined in isolated rabbit gastric mucosa maintained in organ culture. Acetylcholine (10(-8) M) stimulated stimulated both pepsinogen (P less than 0.01) and IF (P less than 0.01) secretion and this stimulation was blocked by atropine. Parasympatholytic agents did not alter unstimulated (basal) secretion of pepsinogen even at high concentrations (atropine, 10(-2) M or propanthelene bromide, 5 X 10(-3) M), however, at these concentrations basal IF secretion was abolished. Histamine (10(-4) and 10(-2) M) had no effect on pepsinogen secretion but stimulated IF secretion (P less than 0.001). Antagonism of H2 receptors by cimetidine reduced both basal and histamine-stimulated IF secretion, but pepsinogen secretion remained unaltered. Under the conditions of the above experiments the gastric mucosal surface was not exposed to HCl but was constantly buffered by culture medium at pH 7.4. When we applied 50 mN HCl to the mucosal surface of the biopsies, pepsinogen secretion doubled (P less than 0.001) but IF secretion was abolished. These studies have clearly documented that: (1) fundamental differences exist in the responses of pepsin and IF secreting cells; (2) H+ ions bathing the mucosal surface of the stomach may influence the results of experiments designed to examine the mechanisms of gastric mucosal macromolecular secretion.

The inhibitory effects of cimetidine on gastric acid and pepsin secretion were studied before and after 1 month of treatment with 300 mg of cimetidine four times a day in 15 male duodenal ulcer patients. Cimetidine inhibited both pentagastrin- and peptone meal-stimulated acid secretion significantly better before, than after, 1 month of treatment. Similarly cimetidine inhibited pentagastrin-stimulated pepsin secretion significantly better before treatment. Meal-stimulated serum gastrin concentrations were significantly higher after treatment. The mechanism(s) of these effects was not apparent.