T. Ihamäki

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.

Long-Term Course and Consequences of Helicobacter pylori gastritis Results of a 32-Year Follow-up Study

BACKGROUND The long-term course of Helicobacter pylori gastritis is not well known because there are few follow-up studies available, and the follow-up time has been short. METHODS The progression of H. pylori infection and chronic gastritis was retrospectively examined in 102 patients followed up for 32 years. In all patients a blind suction biopsy from the corpus mucosa was taken in 1952, and an endoscopic re-examination with biopsy specimens from the antrum and corpus was performed in 1983. RESULTS In the first examination 85 patients (83%) were H. pylori-positive as assessed from Giemsa-stained corpus mucosa specimens as compared with 70 H. pylori-positive patients (69%) at the end of the follow-up (1983). Two of the 17 patients who were initially H. pylori-negative became positive in 1983, implying an infection rate of 0.4% per patient-year. On the other hand, 17 of the 85 patients who were initially H. pylori-positive became negative in 1983, representing a disappearance rate of 0.6%. However, the stomach became completely normal in only eight cases, which represents a healing rate of 0.3% per patient-year. All patients with duodenal ulcer disease were H. pylori-positive at the first examination and remained so during the follow-up. In these patients chronic gastritis affected predominantly the antral mucosa, and corpus atrophy did not develop. Parietal cell antibodies appeared during the follow-up in six cases, and five of them were H. pylori-positive at the first examination. In most of these cases gastritis progressed into severe grades of corpus atrophy accompanied by the disappearance of H. pylori infection and normalization of the antral mucosa. CONCLUSIONS New H. pylori infection and complete healing of infected mucosa may occur in adult life, but this is rare. Duodenal ulcer disease is associated with persistent H. pylori infection and absence of corpus atrophy. The appearance of parietal cell antibodies leads to progression of corpus atrophy and disappearance of H. pylori.

Serum Pepsinogen I and Serum Gastrin in the Screening of Severe Atrophic Corpus Gastritis

The possibilities to screen atrophic corpus gastritis with serum pepsinogen I (S-PGI) and serum gastrin (S-gastrin) concentrations have been studied in 774 subjects: 71 index subjects selected from a general population at random, 353 of their first-degree relatives, 276 first-degree relatives of patients with gastric cancer, 53 patients with pernicious anaemia, and 21 of their relatives. Discrimination function analysis was calculated from members of random and gastric carcinoma families. S-PGI less than 30 ng/ml had a high sensitivity for severe diffuse atrophic corpus gastritis (SDAG) alone (89.5%) and SDAG + severe patchy atrophic corpus gastritis (SPAG) (89.1%). Respective figures for specificity were 91.5% and 94.8%. The discriminatory power of S-PGI less than 30 ng/ml and S-PGI less than 25 ng/ml was of the same order. The sensitivity of low S-PGI decreased sharply in detection of slighter forms of atrophic corpus gastritis. The sensitivity of S-gastrin greater than 100 pmol/l to discriminate SDAG was 57.9% and SDAG+SPAG 58.7%. Respective figures for specificity were 90.2% and 92.2%. Diffuse and patchy atrophic changes behaved similarly regarding S-PGI and S-gastrin mean concentrations. Accordingly, the biopsy specimen with the severest atrophic changes indicates the degree of atrophy, which associates closely with the changes in S-PGI and S-gastrin. In conclusion, severe atrophic (diffuse or patchy) corpus gastritis may be screened from a general population with high sensitivity and specificity by low S-PGI less than 30 ng/ml, whereas an increased level of S-gastrin is too insensitive for this.

Morphological, Functional and Immunological State of the Gastric Mucosa in Gastric Carcinoma Families: Comparison with a Computer-matched Family Sample

Three hundred and one first-degree relatives (series) of 73 gastric carcinoma patients and 358 control relatives (controls) of 73 computer-matched probands from a general population were studied by direct-vision gastric biopsy and functional and immunological examinations. The controls were representative of the series with respect to age, sex, birth and dwelling place, and relationship of the relatives. Series and controls behaved similarly as to total prevalence of gastritis, age and sex distribution of gastritis, serum gastrin level, and circulating gastric antibodies. On the other hand, the total prevalence of hyperplastic polyps, atrophic gastritis of the body and antrum, severe atrophic gastritis of the body, intestinal metaplasia, epithelial atypia, and achlorhydria was significantly higher in the series than in the controls. In subjects below 50 years of age the prevalence of severe atrophic gastritis of the body, intestinal metaplasia, and epithelial atypia was also significantly higher in the series. In addition, the mean age of the subjects with atrophic gastritis, intestinal metaplasia, epithelial atypia, and achlorhydria was lower in the series than in controls; however, significant differences were found only in female subjects with epithelial atypia and atrophic gastritis of the body. The results suggest that the prevalence of signs often considered premalignant is significantly higher in carcinoma relatives than in controls and that these signs show a trend to occur at an earlier age in carcinoma relatives. This could explain the significantly higher than expected death rate from gastric carcinoma in close relatives with this disease, found in the present and in other series.

An appraisal of tests for severe atrophic gastritis in relatives of patients with pernicious anemia.

The sensitivities, specificities, and predictive values of parietal cell antibody, serum gastrin, and serum pepsinogen I (PG I) for severe atrophic gastritis of the oxyntic gland mucosa have been determined in 171 first-degree relatives of 62 patients with pernicious anemia. Parietal cell antibody had the lowest sensitivity (65%), specificity (87%), and predictive value (44%). A low serum PG I and a high serum gastrin had identical specificities (97%), and similar predictive values (84 vs 83%), but the sensitivity of a low serum PG I was greater than that of a high serum gastrin (91 vs 83%). Parietal cell antibody was found in 19 of 148 relatives without severe atrophic gastritis and occurred as an isolated finding in 17. In contrast, 14 of the 15 relatives with severe atrophic gastritis who had parietal cell antibody also had a high serum gastrin and a low serum PG I. A high serum gastrin together with a low serum PG I had a specificity of 100%. The results recommend serum PG I and serum gastrin, but not parietal cell antibody, as tests for severe atrophic gastritis in relatives of patients with pernicious anemia.

Gastric Morphology, Function, and Immunology in First-degree Relatives of Probands with Pernicious Anemia and Controls

Gastric morphology, function, and immunology was studied in 68 patients with pernicious anemia (PA), 183 of their first-degree relatives, and 354 control subjects. The PA relatives and controls were comparable in age and sex distribution. In both groups, mean gastric acid output decreased and mean fasting serum gastrin levels and the prevalence of atrophic gastritis increased with age. The total prevalence of chronic gastritis was similar in the two groups, but severe atrophic gastritis of the body of the stomach (AGB), achlorhydria, parietal cell antibodies, and a raised fasting serum gastrin level were significantly more common in PA relatives than in controls. Of the PA relatives 23 had severe AGB which was indistinguishable from the gastric mucosal lesion found in PA probands and was, as a rule, accompanied by several other characteristics of type A gastritis. These included a normal antrum (78%), slight or absent inflammatory cell infiltration in the gastric mucosa (70%), achlorhydria (91%), high fasting serum gastrin level (83%), parietal cell antibodies (65%), and intrinsic factor antibodies (22%). The mean age and the proportion of subjects with slight and moderate AGB of all AGB subjects was significantly lower in PA relatives than in controls. This suggests an early onset and a rapid progression from mild to severe AGB in PA relatives. Thus, the PA relatives appear to consist of two populations, one with a high and one with little or no proneness to severe AGB. This bimodal distribution suggests the participation of a single major factor, probably genetic, in the pathogenesis of severe AGB in PA relatives.

Age- and Sex-Related Behaviour of Gastric Acid Secretion at the Population Level

Pentagastrin-stimulated gastric acid output and the histology of the antral and body mucosa were examined in 72 computer-selected probands and their 365 relatives, altogether 437 cases. The frequencies of upper abdominal complaints, peptic ulcer and hiatal hernia, and blood group distribution were comparable with those of the population at large. Acid output, expressed as mmol/h, mmol/h/kg of total body weight (TBW), mmol/h/kg of lean body mass (LBM), and mmol/h/kg of fat-free body weight (FFB), correlated with the changes in the body mucosa but not with those in the antrum. Acid output was lower in females than in males when expressed as mmol/h or mmol/h TBW but not when expressed in terms of FFB, which better than LBM accounts for the variation in the gastric surface area and, in this manner, for that of the parietal cell mass. This suggests that the lower acid output in females is due to a smaller gastric surface area and correspondingly smaller parietal cell mass rather than to a lower reactivity of the cells to stimulation. Acid output decreased with increasing age in both sexes, and this was due to a concomitant increase in the incidence and severity of atrophic changes in the body mucosa. An age-related decrease in acid output was not seen in males with a normal body mucosa. In females with a normal body mucosa, however, output expressed in terms of FFB showed a significant increase with age. The reason for this increase is not clear. In males and females with superficial gastritis of the body mucosa acid output decreased with increasing age regardless of the formulation used.

Course of antrum and body gastritis in pernicious anemia families

The course of antrum and body gastritis was studied using an essentially linear multicompartmental model in pernicious anemia probands, their first-degree relatives, and controls consisting of a representative family sample of a large Finnish population. Our earlier dynamic approach showed that progression of body gastritis was virtually identical in a series followed up with biopsies and in cross-comparison analyses, indicating that cross-sectional data can be used for dynamic analyses at a population level. The collected data fitted a model which consisted of stepwise progression of body gastritis to severe atrophy, of corresponding progressive steps for antral gastritis, and of regression of the antral changes after the end-stage of the body process had been reached. In addition, acceleration of the progression of gastritis in older subjects had to be taken into account in the model construction. The main findings which characterized pernicious anemia probands and their close relatives were: (1) a rapid overall progression of body gastritis particularly after 50 years of age; (2) a very rapid progression of body atrophy in its final stages, which was unrelated to age; (3) the occurrence of juvenile severe body atrophy; and (4) the healing of antral gastritis which was most marked at the stage of superficial gastritis. These results may offer a dynamic explanation for the occurrence of severe body atrophy in association with a normal or slightly altered antral mucosa in pernicious anemia and the prepernicious anemia state.

Characteristics of Gastric Mucosa Which Precede Occurrence of Gastric Malignancy: Results of Long-Term Follow-up of Three Family Samples

The aim of the study was to evaluate what family characteristics and what morphological, functional and immunological changes of the gastric mucosa precede the development of gastric malignancy in a follow-up of 11-14 years. The material consisted of 301 first-degree relatives of gastric carcinoma patients, 183 relatives of pernicious anaemia patients, and of 358 control relatives of probands computer matched from the general population by age and sex for the carcinoma probands. All subjects were endoscopically examined in 1973-1976 and followed up to the end of 1987. According to cancer registry data, 11 cases of malignant gastric tumours (9 carcinomas, one carcinoid tumour and one anaplastic tumour with suspicion of Hodgkins disease) had been diagnosed during the follow-up: 6 belonged to gastric carcinoma, 2 to pernicious anaemia and 3 to control families. The occurrence of malignancy was significantly related to the presence of advanced gastritis with atrophy and of intestinal metaplasia before the start of the follow-up. In relatives with achlorhydria and low serum pepsinogen I levels the incidence of malignancy did not significantly differ from that in controls of similar age and sex distribution. The risk of getting malignancy was about four-fold in female members of gastric carcinoma and pernicious anaemia families but was not increased in control families. The risk was increased only in female members and concerned only gastric malignancy being the expected one or even lower than the expected in regard to malignancies of other location.

Progression of Gastritis at a Population Level: Comparison of a Long-Term Follow-up with Stochastic Analysis of Cross-Sectional Data

The applicability of the stochastic theory was tested by comparing dynamic data obtained from a cross-sectional population sample with the progression of gastritis observed during a long-term follow-up study of subjects with originally normal body mucosa or superficial gastritis. A good fit of the follow-up with the basic stochastic assumptions was observed, and the progression of gastritis during the follow-up study was similar to that obtained by the stochastic analysis of the cross-sectional data.