I. Michael Samloff

Relationships Among Serum Pepsinogen I, Serum Pepsinogen II, and Gastric Mucosal Histology: A Study in Relatives of Patients with Pernicious Anemia

To examine the possible effect of gastritis on the endocrine component of pepsinogen secretion, we determined relationships among gastric mucosal histologic characteristics and serum levels of pepsinogen I and pepsinogen II in 170 first-degree relatives of patients with pernicious anemia. Sixtyfour had normal fundic gland mucosa, 66 had superficial gastritis, 17 had mild or moderate atrophic gastritis, and 23 had severe atrophic gastritis. In superficial gastritis, serum pepsinogen I and pepsinogen II were both significantly higher than normal, but the percentage rise in pepsinogen II was significantly greater than the rise in pepsinogen I. In mildl moderate atrophic gastritis, pepsinogen I did not differ from normal, but pepsinogen II was significantly elevated, while in severe atrophic gastritis, pepsinogen II did not differ from normal, but pepsinogen I was significantly decreased. The nonparallel changes in serum pepsinogen I and pepsinogen II levels resulted in a decrease in the pepsinogen I to pepsinogen II ratio from 6.2 ± 0.2 in subjects with normal fundic gland mucosa to 4.3 ± 0.2, 2.9 ± 0.4, and 0.7 ± 0.2, respectively, in those with superficial gastritis, mild to moderate atrophic gastritis, and severe atrophic gastritis. The pepsinogen I to pepsinogen II ratio in combination with the absolute level of serum pepsinogen I correctly predicted the histologic status of the gastric mucosa in 119 of the 170 subjects, 70.0%. The results indicate that (a) increasing severity of gastritis is associated with nonparallel alterations in serum levels of pepsinogen I and pepsinogen II, (b) that these changes lead to a progressive decrease in the pepsinogen I to pepsinogen II ratio, and (c) that the pepsinogen I to pepsinogen II ratio, in combination with pepsinogen I, is predictive of the histologic status of the gastric mucosa.

Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators

The ratio of pepsinogen I to pepsinogen II in the circulation decreases progressively with increasing severity of atrophic gastritis of the fundic gland mucosa. Fasting blood was obtained from 359 free‐living and institutionalized elderly people (age range, 60 to 99 years). A pepsinogen ***I/pepsinogen II ratio less than 2.9, indicating atrophic gastritis, was found in 113 (31.5%) subjects. The prevalence of atrophic gastritis increased significantly with advancing age (P <.05). Within the atrophic gastritis group, 84 had a pepsinogen I level greater than or equal to 20 μg/L, indicating mild to moderate atrophic gastritis, and 29 had a pepsinogen I level less than 20 μg/L, indicating severe atrophic gastritis or gastric atrophy. A significant increase in the prevalences of elevated serum gastrin levels (P <.005), low serum vitamin B12 levels (P <.005), circulating intrinsic factor antibody (P <.005), and anemia (P <.025) was observed with stepwise increases in severity of atrophic gastritis. Subjects with atrophic gastritis exhibited a lower mean serum vitamin B12 level (P <.05) and a higher mean folate level (P <.05), but no difference was detected in mean hemoglobin levels or serum levels of iron, ferritin, retinal or α‐tocopherol. It is concluded that serum pepsinogen I and pepsinogen II levels can be used to determine the prevalence and severity of atrophic gastritis, that atrophic gastritis is common in an elderly population, and that atrophic gastritis is associated with vitamin B12 deficiency and anemia. Further, higher folate levels in atrophic gastritis may be related to an accumulation of 5‐methyl tetrahydrofolate in serum due to vitamin B12 deficiency and/or greater folate synthesis by the intestinal flora resulting from bacterial overgrowth secondary to hypo‐ or achlorhydria.

Duodenal-ulcer disease associated with elevated serum pepsinogen I: an inherited autosomal dominant disorder.

To delineate genetic factors involved in the pathogenesis of duodenal ulcer, serum pepsinogen I levels were determined by radioimmunoassay in two large kindreds with multiple members affected with duodenal ulcer. An elevated serum immunoreactive pepsinogen I concentration (greater than 100 ng per milliliter) segregated as an autosomal dominant trait in these families. Furthermore, 10 of 11 patients with clinical ulcer disease in these families had hyperpepsinogenemia. An elevated serum pepsinogen I concentration appears to be a subclinical marker of the ulcer diathesis in families with this autosomal dominant form of peptic-ulcer disease.

Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells

It has been found by immunohistochemical staining that antigens normally found in gastric and/or intestinal epithelial cells are expressed in most differentiated duct cell carcinomas of the pancreas. Among 88 such tumors, 93% and 92%, respectively, expressed M1 and cathepsin E, markers of gastric surface-foveolar epithelial cells, 51% expressed pepsinogen II, a marker of gastroduodenal mucopeptic cells, 48% expressed CAR-5, a marker of colorectal epithelial cells, and 35% expressed M3SI, a marker of small intestinal goblet cells. Most of the tumors also expressed normal pancreatic duct antigens; 97% expressed DU-PAN-2, and 59% expressed N-terminus gastrin-releasing peptide. In agreement with these findings, electron microscopy revealed malignant cells with fine structural features of gastric foveolar cells, gastric mucopeptic cells, intestinal goblet cells, intestinal columnar cells, pancreatic duct epithelial cells, and cells with features of more than one cell type. Normal pancreatic duct epithelium did not express any marker of gastrointestinal epithelial cells, whereas such benign lesions as mucinous cell hypertrophy and papillary hyperplasia commonly expressed gut-type antigens but rarely expressed pancreatic duct cell markers. By contrast, lesions characterized by atypical papillary hyperplasia commonly expressed both gastric and pancreatic duct cell markers. Metaplastic pyloric-type glands expressed pepsinogen II and, except for their expression of cathepsin E, were indistinguishable from normal pyloric glands. In marked contrast, the immunohistochemical and ultrastructural features of 14 ductuloacinar cell tumors were those of cells lining terminal ductules, centroacinar cells, and/or acinar cells; none expressed any gut-type antigen. The results indicate that gastrointestinal differentiation is common in both benign and malignant lesions of pancreatic duct epithelium and suggest that duct cell carcinomas are histogenetically related to gastric- and intestinal-type metaplastic changes of epithelial cells lining the main and interlobular ducts of the pancreas.

Peptic Ulcer: The Many Proteinases of Aggression

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 pepsinogens I and II and stomach cancer

Prospective epidemiologic studies among Hawaiian Japanese men have shown that a serum pepsinogen I (PG I) level below 20 ng/ml is highly specific for extensive intestinal metaplasia of the stomach and for the intestinal type of stomach cancer. The test, however, shows a low level of sensitivity as a predictor of the intestinal type stomach cancer. Since antralization of the corpus, as encountered in Type A atrophic gastritis and late stage Type B gastritis, results in an increase of PG II relative to PG I, we examined the sensitivity and specificity of the PG I/PG II ratio as a predictor of gastric cancer. Using a cut-off point of 2.0 in the ratio to separate subjects at high and low risk for stomach cancer, we found a modest improvement in the level of sensitivity with a small decrease in specificity. Abnormally low PG I levels and PG I/PG II ratios were associated mainly with advanced stages of the intestinal type of cancer and therefore, are not useful screening tests to identify early cases of gastric cancer. The use of the PG I/PG II ratio resulted in a modest improvement in the level of sensitivity with a small decrease in specificity.

Comparison of Gastric Acid Secretion Rates and Serum Pepsin ogen I and II Concentrations in Occidental and Oriental Duodenal Ulcer Patients

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 malabsorption in atrophic gastritis

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.

Serum Group I Pepsinogen Levels and Their Relation to Gastric Acid Secretion in Patients with and without Recurrent Ulcer

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.

Human pepsinogen C (progastricsin) polymorphism: Evidence for a single locus located at 6p21.1-pter ☆ ☆☆

A series of six clones containing the entire human pepsinogen C gene (PGC) was identified in a cosmid vector library by using cDNA and oligonucleotide probes. The 10.7-kb PGC gene includes nine exons and exhibits a high degree of sequence identity (60%) with the functionally related pepsinogen A genes. The predicted amino acid sequence was identical with the partial amino-terminal and carboxyl-terminal sequences of purified pepsinogen C. An informative restriction fragment length polymorphism was detected with several restriction enzymes and involved an insertion or deletion of 100 bp of intron sequence located between exons 7 and 8. Evidence that there is only a single PGC gene in humans is presented. The PGC gene and the prolactin gene were regionally localized to 6p21.1-pter by analysis of mouse X human somatic cell hybrids.