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Serum alpha 1-antitrypsin (A1AT) allo- and phenotypes (including M1, M2 and M3 alleles) were studied in 99 patients with gastric ulcer (GU) and 56 patients with duodenal ulcer (DU) using agarose isoelectric focusing. The results were compared with the A1AT data of a random population sample of similar genetic background (1422 persons). An increase in M2 allotype and M1M2 phenotype as well as a decrease in Z allotype of A1AT was seen in GU in comparison to DU and the random population. There were no particular clinical features which would distinguish patients with M2 allotype from the remainder of the GU group. However, a trend toward elevated serum pepsinogen I and II levels in patients with M2 allotype was seen. When the pepsinogen levels were compared in the GU patient groups with and without M2 allotype, matched between themselves by the state of the gastric mucosa, a statistically significant difference was revealed between pepsinogen II levels in these two groups. No associations were found between DU and any of the A1AT phenotypes.

The behaviour of acid secretion, serum pepsinogen I and II (PG I and PG II) and morphology of the gastric mucosa were analyzed in 59 duodenal ulcer probands (DU probands), their 199 first-degree relatives and 228 control subjects. DU probands had as a rule antral gastritis with normal or slightly altered corpus mucosa, and higher mean peak acid output (PAO), PG I and II levels than their relatives and controls. Sibs of DU probands differed from their controls mainly with regard to morphology which showed features characteristic of DU probands, i.e. antral gastritis with normal or slightly altered corpus mucosa. Moreover, high PAO levels were found highly significantly more often in sibs of DU probands (13%) than in controls (6%). Likewise, the prevalence of endoscopic signs of active or past duodenal ulcer were present in sibs highly significantly more often than in controls and they accumulated in the subgroup of sibs with high PAO or PG I levels. It seems probable that the occurrence of high PAO and PG I levels in sibs of DU probands can be considered as signs of increased liability to duodenal ulcer. PAO and PG I were as expected significantly higher in male than in female probands, relatives and controls. Exclusion of cases of corpus gastritis decreased the levels but the sex difference persisted. PAO, PG I and II revealed a significant increase of the levels in middle age followed in older age in case of PAO and PG I by a significant decrease. The decrease was abolished when the cases of corpus gastritis were excluded suggesting an effect of gastritis. However, the earlier increase of the levels remained virtually unaffected although there was a uniform decrease of the mean values. This suggests the participation of factors unrelated to gastritis. The nature of the factors remains unknown, but literature data and data derived from our recent study suggest involvement of anatomical factors such as an increase in the size of acid and PG I secreting area.

Acid secretion and basal serum pepsinogen I and II concentrations were measured in 14 duodenal ulcer patients before and at intervals up to six years after proximal gastric vagotomy. Vagotomy led to significant and long-standing reductions in basal, vagally mediated (induced by sham feeding), and peak pentagastrin-stimulated acid secretion. Serum pepsinogen I concentrations also decreased significantly after vagotomy but to a significantly lesser extent than acid secretion. There was no correlation between serum pepsinogen I concentrations and peak acid secretion, either before or after vagotomy. Serum pepsinogen II concentrations decreased only slightly and transiently after vagotomy. Thus, proximal gastric vagotomy reduces acid hypersecretion and pepsinogen I hypersecretion, but not pepsinogen II hypersecretion, in duodenal ulcer patients.

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.

In a search for a genetic marker of duodenal ulcer, we measured serum pepsinogen I levels in 168 ulcer patients and 151 of their clinically normal siblings. The ulcer patients tended to have either hyperpepsinogenemia I (pepsinogen I, greater than or equal to 100 ng/mL) or a normal level on a familial basis. Further evidence supporting this separation was the finding that the mean serum pepsinogen I level in the clinically normal siblings of the hyperpepsinogenemic patients was 91.2 ng/mL, significantly higher than the mean level (63.1 ng/mL) in the normal siblings of the normopepsinogenemic I patients. In the hyperpepsinogenemic I families the results of segregation analysis of an elevated pepsinogen I were consistent with autosomal-dominant inheritance of this trait. The genetic basis of normopepsinogenemic I duodenal ulcer was also shown by the familial aggregation of this disorder. These data provide direct evidence for genetic heterogeneity of duodenal ulcer disease.

Antral G-cell hyperfunction is a rare cause of hypergastrinemia, hyperchlorhydria, and duodenal ulcer disease. We found evidence for a familial basis for this disorder. The probands were two young men with aggressive duodenal ulcer who had basal and postprandial hypergastrinemia, hyperpepsinogenemia I, and basal and pentagastrin-stimulated hyperchlorhydria. All characteristics returned to normal after antrectomy and vagotomy. Antral gastrin concentrations and quantitative G-cell counts were normal, indicating hyperfunction of G-cells rather than hyperplasia. Four of 10 first-degree relatives of the two patients shared with them the combination of postprandial hypergastrinemia and hyperpepsinogenemia I. The aggregation of these abnormalities in tow families, each identified by a proband with hypergastrinemic, hyperpepsinogenemic l duodenal ulcer, suggests that antral G-cell hyperfunction may have a genetic basis.

The CURE peptic ulcer clinic started in April 1974. Patients (mostly veterans) with documented ulcer disease were interviewed regularly and inpatient hospitalizations were reviewed for follow-up periods of up to 6 years. Data from 245 male ulcer patients, 190 with duodenal ulcer alone and 55 with both documented duodenal ulcer (DU) and gastric ulcer (GU), were analyzed to assess the natural history of ulcer disease and factors predicting the severity of its course. Eleven percent of clinic patients had a complication (bleeding requiring a transfusion, perforation, or obstruction) during follow-up. Complication rates were about 2.7% per year for those with no prior complication, and about 5% per year for those with a prior complication. No patient variables or ulcer markers were related to the likelihood of a complication. Patients with both DU and GU were similar to patients with DU alone on many background variables, but the combined ulcer group had a significantly higher frequency of blood group nonsecretors, increased incidence of cigarette smoking, and greater frequency of complications or ulcer hospitalization prior to entry into the study and during follow-up. These factors, together with our failure to find differences in aggressive factors (acid output and PGI), suggests that DU + GU represents a different disease entity marked by additional defects in mucosal defense.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

120 patients were randomly allocated to receive ranitidine 150 mg twice daily or a tri-potassium di-citrato bismuthate (TDB) tablet four times a day in a trial comparing the effects of these drugs in the short-term healing and post-healing relapse rates of duodenal ulceration. At 4 weeks 81% of those on ranitidine and 90% of those on TDB had healed ulcer craters. At 8 weeks 97% of those on ranitidine and 97% of those on TDB had healed. These differences are not significant. After ulcer healing, the cumulative rates of relapse, as determined endoscopically, for symptomatic and symptomless ulcers were 74% for ranitidine and 41% for TDB at 4 months (p less than 0.001), 87% for ranitidine and 55% for TDB at 8 months (p less than 0.001), and 89% for ranitidine and 62% for TDB at 12 months (p less than 0.001). Females had significantly lower relapse rates than males. In the ranitidine group smokers had a higher rate of early relapse and failure to remain healed at 12 months than did non-smokers; no such difference occurred in the TDB-treated group.

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.

In a randomized double blind multicenter trial, patients treated with cimetidine (800 or 1200 mg daily) or an intensive regimen of Al-Mg antacid (210 ml daily) had similar rates of duodenal ulcer healing and pain relief. After 4 weeks of treatment, the proportion of patients with ulcer healing by endoscopy were: cimetidine (1200 mg), 21 of 33 (64 percent); cimetidine (800 mg), 19 of 32 (59 percent); and antacids, 15 of 29 (52 percent). These proportions did not differ significantly. Eighty per cent of cimetidine-treated patients became asymptomatic by week 4, as did 63 percent of antacid-treated patients (P greater than 0.1). No untoward effects were observed during cimetidine treatment. Twenty-seven per cent of antacid-treated patients reported diarrhea.

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.

The first-degree relatives of duodenal ulcer patients and of control probands were evaluated clinically and by gastroduodenal endoscopy for prevalence of duodenal ulcer. The control probands were randomly selected from a control population. 199 relatives of 51 duodenal ulcer probands were interviewed, and 154 of these were endoscoped. 154 control relatives who had been endoscoped were matched with the DU relatives according to sex and age. Endoscopic evidence of present or past duodenal or pyloric ulcer was present in 20 (13.0%) of the DU relatives and in only 6 (3.9%) of the control relatives (p less than 0.01). The frequency of macroscopic duodenitis and gastric erosions was also significantly higher (p less than 0.05) in DU relatives than in controls. A history of epigastric pain was obtained in 54 (35.1%) of endoscoped DU relatives and in 24 (15.6%) of control relatives (p less than 0.01). This study has shown an increased prevalence of endoscopic evidence of duodenal ulcer in the first-degree relatives of duodenal ulcer patients. The finding that duodenitis is also more prevalent in DU relatives than in controls support the view that duodenitis is linked with duodenal ulcer.

The prevalence of antral and body gastritis was determined in 30 duodenal ulcer patients and in 143 of their first-degree relatives, and compared by conventional mathematical and stochastic analyses with data on gastritis in a representative Finnish population sample. For conventional analysis, the controls for the duodenal ulcer patients and for the duodenal ulcer relatives, were matched for age and sex. For stochastic analysis, the duodenal ulcer patients and their 99 siblings were compared with the total control population of 434 subjects. The prevalence of gastritis affecting mainly the antral mucosa, and both antral and body mucosa to a similar extent was significantly higher in duodenal ulcer patients than in both controls and in relatives. The prevalence of antral and body gastritis in DU relatives and their controls was similar. However, the prevalence of subjects with normal antral and body mucosa was significantly lower. Stochastic analysis revealed more rapid progression of antral gastritis with age in the duodenal ulcer patients than in their siblings or controls and less rapid progression of body gastritis. The overall progression of antral and body gastritis was similar in DU siblings and their controls, but a dichotomy in the mean antral gastritis score of DU sibships was found, indicating high and low antral gastritis liability subgroups. The mean score of DU sibships having a mean age of less than 50 years behaved dynamically like DU patients, while the mean scores of sibships with a higher mean age had a low liability to develop antral gastritis. Most duodenal ulcer siblings who themselves had a duodenal ulcer, ulcer scar or duodenitis were found in the "high antral gastritis liability" subgroup.

Duodenal ulcer has not been observed in full-heritage Pima Indians, while gastric cancer is relatively frequent. To investigate possible underlying factors for this phenomenon, we determined gastric acid output, gastric emptying rate, and plasma levels of gastrin, pepsinogen I, and pepsinogen II in apparently healthy Pima Indians and in Caucasian controls. The Pimas had significantly lower basal and stimulated outputs of gastric acid and higher fasting and postprandial plasma gastrin concentrations than the Caucasians. Plasma pepsinogen I levels were similar in the two groups, but plasma pepsinogen II was significantly higher and the ratio of pepsinogen I to pepsinogen II was significantly lower in the Pima Indians. In addition, gastric emptying of acaloric liquid meal was significantly delayed in the Pimas. The results suggest that the absence of duodenal ulcer in Pima Indians may be related to low gastric acid production and a slow rate of gastric emptying in this population. The associated findings of hypergastrinemia, hyperpepsinogenemia II, and a low ratio of pepsinogen I to pepsinogen II suggest that the hypochlorhydria may reflect an increased prevalence of chronic gastritis in full-heritage Pima Indians. This, in turn, could represent a risk factor for the development of gastric cancer in this population.

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.