P. Sipponen

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

BACKGROUNDnThe 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.nnnMETHODSnThe 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.nnnRESULTSnIn 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.nnnCONCLUSIONSnNew 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.

Helicobacter pylori Eradication Has the Potential to Prevent Gastric Cancer: A State-of-the-Art Critique

Helicobacter pylori infection continues to play a key role in gastric diseases. Colonization of the gastric mucosa with the bacterium invariably results in the development of chronic gastritis and subsets of patients have a progression of the chronic gastritis to either ulcer or cancer. Epidemiological evidence indicates that the proportion of all gastric cancers attributable to H. pylori infection, and hence potentially preventable upon elimination of this risk factor, is somewhere in the range of 60% to 90%. This portends significant benefit in terms of morbidity and mortality, not least in populations with high prevalence of H. pylori infection coupled with high incidence of gastric cancer. The effect of prophylactic H. pylori eradication on gastric cancer incidence in humans remains unknown, however. Results from randomized trials are eagerly awaited, but availability of strong conclusive results may take many years. A growing number of studies show considerable variation in risk for gastric cancer development, depending on H. pylori strain type and the genetic predisposition of the host. There is also a remote possibility that elimination of the infection may have adverse health implications (e.g., antibiotic resistance), and therefore “simple” risk stratification and targeted chemoprevention is required. Based on “in depth” evidence presented at this workshop, the majority of the scientific task force favored a search-and-treat strategy in first-degree relatives of gastric cancer patients and an overwhelming majority felt that a more general screen-and-treat strategy should be focused in the first instance on a population with a high incidence of H. pylori-associated diseases.

Disappearance of gastritis after eradication of Helicobacter pylori : a morphometric study

Helicobacter pylori infection is strongly associated with and is considered a common cause of gastritis. To study the relationship between H. pylori and gastritis, we examined whether a reduction occurs in acute granulocytic and chronic mononuclear inflammation of gastric mucosa after eradication therapy. The examination is based on morphometric counting and on semiquantitative estimation of the density of the inflammatory cells in endoscopic biopsy specimens from antrum and corpus. The series consisted of 23 consecutive outpatients with H. pylori-associated gastritis who received a 2-week course of triple therapy with colloidal bismuth subcitrate, amoxicillin, and metronidazole and who underwent an endoscopic follow-up for 6 weeks, 6 months (23 patients), and 12 months (21 patients). The eradication was successful in 20 patients (responders), who also remained H. pylori-free for 6 months, and in 18 examined patients for 12 months but was unsuccessful in 3 patients (non-responders). Both acute and chronic inflammation decreased significantly in intensity in responders in the follow-up. The acute inflammation had already disappeared at a 6-week control. The reduction in chronic inflammation was slower and occurred gradually within the study. At the 12-month follow-up, the corpus mucosa was interpreted as normal in all 18 patients studied, and the antral mucosa was interpreted as normal in 10 (56%) patients. No significant reduction in intensity of gastritis was found in the 3 non-responders or the 23 matched, untreated controls. We conclude that the eradication of H. pylori results in a disappearance of both acute and chronic gastritis. This supports the view that H. pylori plays a causal role in the pathogenesis of chronic gastritis.

Cumulative 10-Year Risk of Symptomatic Duodenal and Gastric Ulcer in Patients with or without Chronic Gastritis: A Clinical Follow-up Study of 454 Outpatients

The cumulative rate of symptomatic peptic ulcer (PU) was examined in a 10-year clinical follow-up study of 454 consecutive outpatients who had undergone diagnostic gastroscopy, from whom routine biopsy specimens were taken from the antral and corpus mucosa, and who were found to be ulcer-free before and at the time of this initial gastroscopy. During the follow-up period 34 (11%) of 321 patients who showed gastritis in the biopsy specimens at the initial gastroscopy had contracted symptomatic PU (18, 5, 7, and 4 cases of duodenal, pyloric, antral, and angular or corpus ulcer, respectively), which was verified by endoscopy. Only 1 (0.8%) of 133 patients with normal antral and corpus mucosa had contracted PU. It was calculated that the 10-year cumulative probability of PU was 10.6% (95% confidence interval (CI95), 7.2-14.0%) in the patients with gastritis, whereas this probability was only 0.8% (0-2.2%) in the patients who had normal antral and corpus mucosa in the initial specimens. The cumulative probability of PU was found to be highest, 27.3% (1.0-53.6%), in middle-aged men (41-60 years of age) who had chronic antral gastritis or chronic pangastritis (gastritis in both antrum and corpus). It is concluded that chronic gastritis precedes the appearance of PU and that the cumulative 10-year risk of PU is very low when both antral and corpus mucosa are normal but may be high if chronic gastritis is present.

Implications of Serum Pepsinogen I in Early Endoscopic Diagnosis of Gastric Cancer and Dysplasia

K. Varis, P. Sipponen, F. Laxén, I. M. Samloff, J. K. Huttunen, P. R. Taylor, O. P. Heinonen, D. Albanes, N. Sande, J. Virtamo, M. Härkönen & the Helsinki Gastritis Study Group* National Public Health Institute; Dept. of Public Health, University of Helsinki; and Dept. of Clinical Chemistry, Helsinki University Central Hospital; Helsinki, and Jorvi Hospital, Espoo, Finland, and V. A. Medical Center, Sepulveda, California, and National Cancer Institute, Bethesda, Maryland, USABACKGROUND AND AIMSnThe risk of gastric cancer (GCA) is increased in atrophic gastritis. A low serum pepsinogen group I (SPGI) level is a good serologic indicator of atrophic gastritis of the gastric corpus and fundus, and can be used for diagnosis of subjects with atrophic gastritis and of increased risk for GCA. The present study was undertaken to investigate whether SPGI assay and a diagnostic gastroscopy could enable the diagnosis of GCA at an early stage.nnnMATERIAL AND METHODSnThe study was carried out as part of the Alpha-Tocopherol, Beta-Carotene Cancer prevention study (ATBC study) in Finland, in which 22,436 male smokers aged 50-69 years were screened by SPGI. Low SPGI levels (< 25 microg/l) were found in 2196 (9.8%) men. Upper GI endoscopy (gastroscopy) was performed in 1344 men (61%) and 78% of these had moderate or severe atrophic corpus gastritis in endoscopic biopsies. A control series of 136 men from the ATBC study cohort with abdominal symptoms, but with SPGI > or = 50 microg/l were similarly endoscopied, and 2.2% of these had corpus atrophy.nnnRESULTSnNeoplastic alterations were found in 63 (4.7%; 95% CI: 3.6%-5.8%) of the 1344 endoscopied men with low SPGI levels. Of these, 42 were definite dysplasias of low grade, 7 dysplasias of high grade, 11 invasive carcinomas, of which 7 were early cancers, and 3 carcinoid tumors. In the control series, 1 man (0.7%) of the 136 men had a definite low-grade dysplasia. Thus, 18 (1.3%; 95% CI 0.7%-2.0%) cases with severe neoplastic lesions (4 advanced cancers, 7 early cancers and 7 dysplasias of high grade) were found in the low SPGI group, but there were none in the control group. All four patients with advanced cancer died from the malignancy within 5 years (mean survival time 2.5 years), whereas surgical treatment in all those with early cancer or high-grade dysplasia was curative. One of the seven patients with early cancer and two of the seven with high-grade dysplasia died within 5 years, but none died from the gastric cancer. Thus, curative treatment was given to 14 of 18 men in whom a malignant lesion was found in gastroscopy. This is about 15% of all gastric cancer cases (92 cases) which were diagnosed within 5 years after SPGI screening in the 22,436 men. Among the gastric cancer cases of the main ATBC study, the 5-year survival rate was 33% (85% of the non-survivors died from gastric cancer).nnnCONCLUSIONSnWe conclude that assay of SPGI followed by endoscopy is an approach which can enable the early diagnosis of gastric cancer at a curable stage.

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.

Gastric Cancer and Premalignant Lesions in Atrophic Gastritis: A Controlled Trial on the Effect of Supplementation with Alpha-Tocopherol and Beta-Carotene

Background: Vitamin E and beta-carotene are considered to decrease the risk of gastric cancer both in humans and in laboratory animals. We studied the effect of dietary supplementation with alpha-tocopherol and beta-carotene on the end-of-trial prevalence of premalignant and malignant lesions of the stomach in older men with atrophic gastritis. Methods: The study was carried out within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC study) in Finland, in which 29,133 male smokers aged 50-69 years were randomly assigned to receive daily 50 mg alpha-tocopherol, 20 mg beta-carotene, both of these agents, or placebo, for 5-8 years. Serum pepsinogen was determined at base line and after 3 years supplementation to find men with atrophic gastritis. A low serum pepsinogen I level, indicating atrophic gastritis of the corpus area of the stomach, was found in 2132 men. These men were invited to have upper gastrointestinal endoscopy (gastroscopy), which was performed on 1344 subjects after a media...

Atrophic chronic gastritis and intestinal metaplasia in gastric carcinoma. Comparison with a representative population sample

The occurrence of chronic gastritis and intestinal metaplasia (IM) was studied in 257 patients with gastric carcinoma (GC). In all cases biopsies were available from the benign mucosal area adjacent to the tumor, and in 139 patients from the antrum and/or body mucosa outside the tumor. The results were compared with endoscopically and bioptically examined noncancer controls representing a large Finnish population sample. For every GC patient, a control subject was matched by age and sex. In addition, a mean age‐adjusted score (AAS) of chronic gastritis, which expresses the progression of gastritis in GC patients as compared with that in the general population, was calculated for GC patients. The prevalences of chronic and atrophic gastritis in the antrum and body mucosa were similar in GC patients and controls when carcinoma cases were not more specifically classified according to histologic type or location of tumors. On the other hand, the location of the tumor showed a significant relation to gastritis: the progression of gastritis was more rapid (high mean AAS value) and the prevalence of atrophic gastritis was higher in the tumor‐affected area (i.e., in the antrum in patients with antral [distal] tumors; in the body in patients with body [proximal] tumors), than in the general population, but were similar in the tumor‐free area in both GC patients and controls. In the intestinal type of GC (IGC), the prevalence of chronic gastritis was higher and its progression was more rapid than in controls. In the diffuse type of GC (DGC), these correlations were less distinct. In GC patients, the IM adjacent to and outside the tumor area was significantly more common and extensive than in the corresponding area of controls, and a significant positive correlation was present between the location of the tumor and the distribution of IM. Like gastritis, the IM showed a closer relationship to IGC than to DGC. In all cases of GC and particularly of IGC, the antral mucosa tended to be more severely affected by gastritis and IM than the body mucosa, i.e., the prevailing type of gastritis found in this GC series was that morphologically corresponding to the so‐called B‐type of chronic gastritis.

Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection

Background: Deficiency of vitamin B12 raises the serum and tissue levels of homocysteine. Atrophic corpus gastritis results in impaired secretion of intrinsic factor and may lead to malabsorption of vitamin B12 in the intestine. We examined how common an undiagnosed vitamin B12 deficiency is among elderly men in the general population and, in particular, how often this deficiency is related to atrophic corpus gastritis. Methods: The serum level of pepsinogen I (S‐PGI) was assayed in a population‐based sample of 12,252 men (age 51–65 years) from two cities in Finland. In this sample, all 635 men with S‐PGIu2005<u200525u2005μg/l formed Series A (‘males with atrophic corpus gastritis’). Series C (controls – ‘males without atrophic corpus gastritis)’ with a non‐atrophic gastric corpus was formed as a random sample of men (nu2005=u2005402) with S‐PGIu2005≥u200550u2005μg/l. Serum levels of vitamin B12 (S‐B12), folate (S‐Fol), total homocysteine (S‐Hcy) and Helicobacter pylori antibodies (S‐HpAb) were assayed in all, or in large subsamples, of the men in Series A and C. Results: The men in Series A had significantly lower S‐B12 and S‐Fol levels than those in Series C. In Series A, 172 of 613 men tested (28%) had S‐B12u2005<u2005170u2005pmol/l, and 133 men (22%) had S‐B12 in the range 170–219u2005pmol/l. The corresponding prevalences were 7% (Pu2005<u20050.001) and 17% (Pu2005<u20050.001) in Series C, respectively. The mean S‐Hcy was significantly higher in Series A in men with low S‐B12 than the mean S‐Hcy in Series C in men with normal S‐B12. The prevalence of S‐Hcyu2005>u200515u2005μmol/l was 27% in Series A and 15% in Series C (Pu2005<u20050.05; χ 2 u2005=u20054.63). Among subjects with S‐B12u2005<u2005220u2005pmol/l, 46% (104 of 226 men tested) in Series A and 16% (16 of 99) in Series C had S‐Hcyu2005≥u200515u2005μmol/l (Pu2005<u20050.001). The mean S‐Hcy was significantly (Pu2005<u20050.001) higher in men with S‐B12 in the range 170–219u2005pmol/l in Series A (mean 14.6u2005±u20055.0u2005μmol/l) than in Series C (11.3u2005± 3.0u2005μmol/l). It was extrapolated that 2.5% of men in the age group 51–65 years in the present study population had a low S‐B12 (<220u2005pmol/l) level that associated with atrophic corpus gastritis. Of these men, 72% (128 of 179 tested) had an elevated S‐HpAb level. Conclusions: Low S‐B12 related to atrophic corpus gastritis is relatively common (prevalence 2.5%) among elderly males in the general population. An ongoing H. pylori infection occurs in three‐fourths of these cases.

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.