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.

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 Hodgkin's 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.

Enrichment of combined antral and corpus atrophic gastritis ("combined AG") in sibs of gastric carcinoma patients.

The occurrence of different combinations of antral and corpus atrophic gastritis (AG) was studied in 127 sibs and 159 children of 73 gastric carcinoma patients. Seventy-three control probands, age- and sex-matched for the carcinoma probands, and their 379 first-degree relatives were used as controls. Sibs of gastric carcinoma patients revealed a significant enrichment of AG affecting simultaneously both antrum and corpus (combined AG), while no such enrichment could be demonstrated in children, who behaved on the whole similarly to the controls. In addition, sibs of gastric carcinoma patients showed a significant aggregation of combined AG also when compared with children of similar age. This suggests that genetic factors in addition to environmental ones participate in the accumulation of combined AG in sibs. The lack of phenotype AB in children excludes the possibility of dominant Mendelian inheritance, but leaves the possibility of a recessive autosomal or multigenetic inheritance. The enrichment of combined AG in sibs of gastric carcinoma patients could be one of the factors involved in the increased liability of close relatives of gastric carcinoma patients to contract gastric malignancy.

Chronic gastritis profiles in sibs of probands calculated to carry a highly increased risk of gastric carcinoma.

Of 1161 subjects consisting of 4 family samples (gastric carcinoma patient relatives, pernicious anaemia, duodenal ulcer and control families) 18 subjects representing 17 families had distinct atrophic changes in the gastric mucosa that were considered on the basis of risk calculations to carry an at least 7-fold risk to develop gastric carcinoma. Twelve of these 18 subjects could be used as probands and their 41 sibs were subjected to a closer statistical analysis. Sibs of probands having a very high relative risk of gastric carcinoma (18-fold or more) differed markedly from the general population. All sibs had some form of atrophic gastritis and there was a significantly higher than expected prevalence of subjects with severe corpus mucosal atrophy. It is concluded that sibs of subjects with severe atrophic changes may carry an increased risk of gastric malignancy.

Increase of serum pepsinogen I with age in females with normal gastric mucosa but not in males, possibly due to increase in acid-pepsin secreting area.

The mean pepsinogen I (PG I) level in a Finnish family sample was different in males and females and the difference was statistically significant. After exclusion of subjects with gastritis there remained 67 females and 68 males with morphologically completely normal antral and corpus mucosa. In females there was a significant increase of PG I with advancing age, the regression coefficient being 0.37 and statistically significant (p less than 0.01). In males no such increase was found, and individual cases revealed an almost random distribution with age. A similar increase with age has been noted in gastric acid output in females but not in males. Assuming that there is a linear relationship between PG I levels and the total chief cell mass, the PG I level would be determined by three main variables: thickness of the glandular layer, density of chief cells, and area occupied by chief cells. Of these variables the thickness and chief cell density showed neither in females nor in males any statistically significant increase with age, leaving the area as the variable which would account for the increase of PG I.

Fasting levels of serum gastrin in different functional and morphologic states of the antrofundal mucosa. An analysis of 860 subjects.

The relationship of fasting serum gastrin (FSG) levels to the histologic state of antral and body mucosa and to the stimulated acid output (PAO) was examined in 860 subjects. The FSG levels correlated with PAO and atrophy of the body mucosa: the FSG increased linearly with an increase in the grade of body atrophy and increased exponentially when the PAO decreased from 'normal' (greater than 10 meq/h) to zero. In subjects with achlorhydria or marked hypochlorhydria (PAO less than 1.1 meq/h) accompanying moderate or severe atrophy in the gastric body mucosa, FSG decreased linearly with increasing grade of atrophy in the antral mucosa. No such relationship between antral atrophy and FSG was found in subjects who had a PAO above 1.1 meq/h or who had non-atrophic gastric body mucosa. We conclude that the state of the antral mucosa influences the FSG level, but only when the function of antral G cells is maximal--that is, in achlorhydric or nearly achlorhydric conditions in which the inhibitory effect of intragastric acidity on the G cells' secretion of gastrin into the circulation is minimal.

Campylobacter pylori is associated with chronic gastritis but not with active peptic ulcer disease.

Campylobacter pylori is supposed to be involved in the pathogenesis of gastroduodenal peptic ulcer diseases and chronic gastritis. In order to study whether the Campylobacter pylori in the stomach of peptic ulcer patients is related to ulcer itself or to a co-existing chronic gastritis, we examined the frequency of the bacteria in Giemsa stained histological sections of biopsy specimens from a series of patients with active peptic ulcer and from series of non-ulcer control subjects. We found no difference in the frequency of Campylobacter- positive cases between ulcer patients and non-ulcer controls when the comparison was done within the same category of chronic gastritis; e.g., within the category of chronic superficial gastritis 74% and 78% of cases showed the bacteria in antral biopsies from ulcer patients and from non-ulcer controls, respectively. In both ulcer patients and control subjects, in similar way in both antral and body mucosa, the Campylobacter pylori was strongly associated with chronic superficial gastritis but was more weakly associated with chronic atrophic gastritis, and the bacteria were only occasionally seen in normal mucosa. We conclude that Campylobacter pylori is associated with chronic gastritis in peptic ulcer patients but is not related to active ulcer.

Prepyloric erosions: an entity of its own among erosive gastric lesions. A morphologic and dynamic study of gastric mucosa in patients with gastric erosions.

The morphology and dynamics of the gastric mucosa were examined in 130 patients with gastric mucosal erosions by using mathematical methods based on stochastic principles. The results were compared with those of controls representative of the general population. The progression of antral gastritis was less rapid in erosion patients than in the controls (p less than 0.001), but body gastritis increased with age, as expected. In patients with prepyloric erosions body gastritis showed less rapid progression with age than in the controls (p less than 0.01) or in other erosion patients (p less than 0.05). Antral gastritis increased, as in the controls, and more rapidly than in other erosion patients (p less than 0.01). The preservation of the body mucosa in patients with prepyloric erosions despite ageing is similar to that seen in patients with duodenal ulcer disease, suggesting a common acid-related pathogenesis.

The sequelae and course of chronic gastritis during a 30- to 34-year bioptic follow-up study.

Three hundred and seventy-seven subjects with different conditions of the gastric body mucosa have been followed up for 30-34 years, first by the 'blind' suction biopsy method and since 1973-1976 by the direct-vision endoscopic method. Body gastritis revealed a distinct worsening trend during the whole follow-up period. However, during the last follow-up period some slowing down of the process was also discernible. In the antrum there was a distinct healing trend during that period. Thus all cases of distinct atrophic gastritis limited to the antrum and found at the re-examination in 1973-1976 had disappeared during the last follow-up period owing to regression of the antral or continuation of the body process. On the other hand, a considerable proportion of cases of diffuse antrofundal atrophic gastritis found in 1973-1976 appeared in 1983-1984 in the 'pure' body atrophic gastritis group, obviously due to regression of the antral process. This indicates the existence of an alternative pathway via diffuse antrofundal atrophic gastritis for the development of atrophic gastritis limited to the body area. The occurrence of parietal cell antibodies was on the whole a poor indicator of the progression of atrophic gastritis. However, the development of the end-stage (severe) atrophic gastritis was significantly associated with their presence. Atrophic changes of the body mucosa were not found in 1983-1984 in any cases of duodenal ulcer disease, whereas in patients with gastric polyps atrophic gastritis affecting only the body was, as a rule, present. No case of gastric carcinoma was detected during the last follow-up examination.

Adrenergic innervation of the human liver. A fluorescence histochemical analysis of clinical liver biopsy specimens.

Liver biopsy specimens from 34 consecutive patients undergoing laparoscopy were processed for glyoxylic acid-induced fluorescence histochemical analysis. Most of the adrenergic nerves were located in the interlobular spaces and confined to blood vessels; no direct functional adrenergic innervation of the hepatocytes could be demonstrated. In eight cases of intrahepatic cholestasis, however, fluorescing varicose adrenergic axons were observed in patchy areas of accumulations of bile pigments. Otherwise the results were analogous in histologically normal liver tissue and in liver disease regardless of the underlying pathology. Methodological difficulties may explain some earlier contradictory results.

Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data.

Relative risk (RR) and cumulative risk of gastric cancer (GCA) were calculated for different grades of atrophic gastritis (AG) of the antrum and body. Cross-sectional data on the occurrence of AG in a representative population sample (371 subjects), and Finnish Cancer Registry data on GCA were used in the calculations. The RR was increased significantly in severe AG of the antrum and the body (18.1 and 4.6 times, respectively), but not significantly in the less severe grades of AG. As a risk factor, severe antral and body gastritis were independent of each other. The cumulative risk, i.e., the probability of contracting GCA within the following 10 years in age groups 50-54 . . . 70-74 years was calculated to vary from 2.3% to 9.3% and from 8.7% to 31.9% in severe antral AG and from 0.9% to 4.5% and from 3.6% to 16.6% in severe body AG in males and females, respectively.

The development of atrophic gastritis in antrum and body in relatives of gastric carcinoma patients and in controls.

The development of atrophic gastritis (AG) in antrum and body was studied in a series consisting of 301 first-degree relatives of 73 gastric carcinoma patients, and in 431 controls, that is, 73 control probands and their 358 first-degree relatives. An analysis was performed in terms of four population pools: subjects with normal mucosa and/or superficial gastritis in antrum and body; AG occurring in the antrum only; AG in the body only; AG present in antrum and body. Antral AG commenced in the patients' teens and progressed at a constant rate up to 55 years, being retarded thereafter with decreasing age-specific prevalence of AG limited to the antral mucosa. The process started later in the body, but its constant-rate progression continued up to old age. In the pool of those subjects who had both antral and body AG the development approximated that seen in the pool with body AG only. The process was qualitatively similar in the Series and in the Controls, but marked differences were observed after the age of 55 years in the transition to the different AG pools.

Susceptibility to chronic gastritis in first degree relatives of gastric carcinoma patients. Effect of histological type of carcinoma and location of tumour.

To elucidate the behaviour of gastritis on a family level 301 first degree relatives of 73 patients with different types of gastric carcinoma have been subjected to a closer analysis. A stochastic mathematical approach was employed in calculating mean score values for each family. In addition, the location of the tumours was taken into account. The findings are compared with those in a series of 358 first-degree relatives (the "controls") of 73 control probands, computer-matched by age and sex to the carcinoma probands. The mean progression of gastritis in the body in the carcinoma families was significantly more rapid than in the controls. In the relatives of probands with diffuse carcinoma the progression of gastritis was significantly more rapid than in the controls in both body and antrum; no such difference was seen in the families of intestinal carcinoma probands. On the other hand, a significant positive correlation was established between the location of all carcinomas and the progression of both antral and body gastritis. Furthermore, intestinal carcinoma of antral location was associated with progression of antral gastritis significantly faster than expected. On the whole, in contrast to the control families, the mean gastritis scores of all carcinoma families were above zero. It is concluded that our earlier finding of a relationship between gastritis and gastric carcinoma at an individual level is also found at a family level.

Upper abdominal complaints and gastritis.

To evaluate the significance of gastritis as a cause of upper abdominal complaints consecutive cases with upper abdominal complaints have been subjected to gastroscopy with biopsies of the antral and body mucosa. The results were compared with those obtained from two representative population samples: one Finnish and one Estonian. The progression of gastritis on an individual level was expressed as an age-adjusted score. It appeared that the progression of gastritis in the series did not significantly differ from the controls, confirming our earlier experience that gastritis as such can hardly be used for the explanation of upper abdominal complaints.

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 explantation 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.

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.

Endoscopic and clinical findings in first-degree relative of duodenal ulcer patients and control subjects.

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.