Lymphocytic gastritis and associated small bowel disease: a diffuse lymphocytic gastroenteropathy?

AIM: To investigate the natural history of lymphocytic gastritis (LG) and its relation to Helicobacter pylori infection and to coeliac disease using serology, duodenal biopsy and a small intestinal permeability test. METHOD: Twenty two patients diagnosed as having LG between 1984 and 1994 were investigated by upper gastrointestinal endoscopy at which gastric and duodenal biopsy specimens were taken for histological assessment and immunohistology. Serum was collected for measurement of anti-H pylori, anti-gliadin and anti-endomysial antibodies. A lactulose/mannitol absorption test was performed within one week of endoscopy. Control groups were studied by histology, serology and permeability tests. RESULTS: Three patients had been recently diagnosed as having LG while 15 still had the condition after a mean of 13.9 (range two to 38) months. LG involved the antrum alone in three patients, antrum and body in seven, body alone in six, and gastric remnant in two. Gastroduodenal intraepithelial lymphocytes (IELs) were T cells and predominantly of T suppressor (CD8) type. Duodenal IELs were increased compared to age/sex matched controls with chronic gastritis. Four patients had duodenal villous atrophy. Four patients no longer had LG after a mean of 29.3 (10-70) months but had increased gastroduodenal IELs. H pylori was present in four (22%) of 18 patients with LG but H pylori serology was positive in 11 (61%) of 18. There was no difference in seropositivity when compared with age/sex matched controls with dyspepsia. Eleven of 20 patients with LG tested had abnormal lactulose/mannitol absorption (v none of 22 controls with chronic gastritis). Four patients with LG, all with villous atrophy, were seropositive for IgA endomysial antibody. CONCLUSIONS: The persistence of LG with time, the association with increased duodenal IELs and abnormal small intestinal permeability suggests LG may be a manifestation of a diffuse lymphocytic gastroenteropathy related to sensitivity to gluten or some other agent.

Prevalence of gastric and duodenal ulcers at endoscopy in Nigerian and British patients.

We compared endoscopic findings in 243 Nigerian and 1867 British patients undergoing endoscopy for similar indications. The Nigerian patients were much younger, 46.5% of them being less than 35 years old whereas the British patients were older, with only 36.2% being less than 35 years old (P = 0.001). Duodenal ulcers were commoner in the Nigerian patients (P = 0.03) and gastric ulcers were also commoner in the Nigerian patients who were less than 35 years old (P = 0.01). There was no difference in the prevalence of gastric nor oesophageal carcinoma in the two groups.

Cell proliferation in Helicobacter pylori associated gastritis and the effect of eradication therapy.

Helicobacter pylori causes chronic (type B) gastritis. The 'intestinal' form of gastric cancer arises against a background of chronic gastritis, and prospective epidemiological studies have shown that H pylori is a major risk factor for this. An increase in mucosal cell proliferation increases the likelihood of a neoplastic clone of epithelial cells emerging where there is chronic epithelial cell injury associated with H pylori gastritis. In vitro bromodeoxyuridine labelling of endoscopic antral biopsy specimens was used to measure mucosal cell proliferation in H pylori associated gastritis before and after therapy for H pylori triple infection. Cell proliferation was increased in H pylori associated gastritis patients compared with normal controls and patients with H pylori negative chronic gastritis (p = 0.0001; Tukey's Studentised range). There was no difference in antral epithelial cell proliferation between duodenal ulcer and non-ulcer subjects infected with H pylori (p = 0.62; Student's t test). Antral mucosal cell proliferation fell four weeks after completing triple therapy, irrespective of whether or not H pylori had been eradicated (p = 0.0001). At retesting six to 18 months later (mean = 12 months), however, those in whom H pylori had not been successfully eradicated showed increased mucosal proliferation compared with both H pylori negative subjects at a similar follow up interval and all cases (whether H pylori positive or negative) four weeks after completion of triple therapy (p = 0.024). These findings suggest that H pylori infection causes increased gastric cell proliferation and in this way may play a part in gastric carcinogenesis.

Systemic and mucosal humoral responses to Helicobacter pylori in gastric cancer.

The systemic IgG response to Helicobacter pylori was examined in 70 patients with gastric cancer. H pylori IgG antibodies were assayed by enzyme linked immunosorbent assay (ELISA), and serological recognition of H pylori antigens was characterised by western blotting. A percentage of 78.5 were seropositive by ELISA. Two of five patients under age 50 were seronegative. Positivity was unrelated to age, sex, tumour type, or site. Ninety one per cent of ELISA positive cancer patients recognised the H pylori cytotoxin associated 120 kilodalton (kD) protein, significantly more than a control group of 47 ELISA positive patients with non-ulcer dyspepsia (72%). Four of 15 ELISA negative cancer patients also showed recognition of this protein in western blots. Mucosal IgA responses to H pylori were examined by immunoblotting supernatants of in vitro cultured resected antral mucosa in an overlapping group of 19 gastric cancer patients. Eighteen had a positive response, including 10 of 11 negative for H pylori by biopsy urease testing. The systemic and local immunoblotting results show that the high seroprevalence of H pylori antibodies detected by ELISA is nevertheless an underestimate of past infection. Dyspepsia screening policies based solely on H pylori ELISA would miss some young patients with gastric cancer. Further study of the relation of the H pylori cytotoxin to gastric precancerous lesions is warranted.

Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations.

Ascorbic acid, the reduced form of vitamin C, may protect against gastric cancer and is secreted by the normal stomach. Secretion is impaired in Helicobacter pylori (H pylori) associated chronic gastritis. This study examined if eradication of H pylori improves gastric juice ascorbate values. Fasting gastric juice and plasma samples were collected at endoscopy from patients participating in trials of H pylori eradication for duodenal ulcer disease and intestinal metaplasia before and up to 15 months after attempted eradication. Ascorbic acid and total vitamin C concentrations were determined by high performance liquid chromatography. In 12 patients in whom H pylori was successfully eradicated gastric juice ascorbate and total vitamin C concentrations and the ratio of juice to plasma vitamin C rose after treatment. Analysis after treatment suggested that the rise was greatest in patients with high final plasma vitamin C concentrations, even though these did not change with treatment. By contrast, in 22 patients in whom H pylori eradication was unsuccessful there were no significant changes in juice or plasma concentrations after treatment. It is concluded that successful eradication of H pylori improves secretion of vitamin C into gastric juice. It is speculated that this increases protection against gastric cancer.

Failure of colonoscopic surveillance in ulcerative colitis.

A prospective surveillance programme for patients with longstanding (> = 8 years), extensive (> = splenic flexure) ulcerative colitis was undertaken between 1978 and 1990. It comprised annual colonoscopy with pancolonic biopsy. One hundred and sixty patients were entered into the programme and had 739 colonoscopies (4.6 colonoscopies per patient; 709 patient years follow up). Eight eight per cent of examinations reached the right colon. There was no procedure related death. One Dukes's A cancer was detected. Forty one patients (25%) defaulted. Of these 25 remain well; 13 are unaccounted for, and one died from colonic cancer. One patient had colectomy for medical reasons, and another died of carcinoma of the pancreas. Retrospectively an additional 16 eligible patients were identified who had not been recruited. Of these, 14 remain well, two are unaccounted for. None developed colonic cancer. Four patients refused colonoscopy. All remain well. Over the same period seven other cases of colonic cancer were found in association with ulcerative colitis, two in patients who had erroneously been diagnosed as having only proctitis and were therefore not entered into the programme, but were found at operation to have total colitis, one in a patient with colitis of seven years duration, and four patients who had previously attended the clinic but had been lost to follow up before 1978 and then had represented with new symptoms during the surveillance period. Thus, of the nine colitis related cancers diagnosed in this centre during the study period only one was detected by the surveillance programme. The results of this large study, a a review of published works, cast doubts on the effectiveness of colonoscopic surveillance programmes in detecting colorectal cancer in patients with ulcerative colitis.

Oral tobramycin in ulcerative colitis: effect on maintenance of remission.

Oral tobramycin for 7 days has been shown to be of benefit as an adjunct to conventional medication in acute ulcerative colitis. Eighty-one patients (40 who had received tobramycin; 41 placebo) who had been enrolled in a double-blind placebo-controlled trial of this drug in acute disease were subsequently followed to determine whether this short-term benefit persisted. Relapse was defined as a liquid stool frequency of three times daily with rectal bleeding. Results were analysed by the log-rank test on Kaplan-Meier survival curves. Treatment failure was defined as a lack of response by the end of the acute trial period, or subsequent relapse. In a second analysis, only those entering remission at the end of the acute trial were considered, and followed to relapse. Although at the start of the follow-up period significantly fewer patients in the tobramycin group had failed (failed: tobramycin 9, placebo 24; not failed tobramycin 31; placebo 17; P = 0.001), the failure-free survival curves subsequently converged and did not differ significantly. After 1 and 2 years, the failure-free survival rates were 40% (S.E. = 7.8%) and 20% (S.E. = 6.3%) for the tobramycin group and 24% (S.E. = 6.7%) and 12% (S.E. = 5.1%) for the placebo group. When only those entering remission were considered, there was no significant difference in the relapse rates in the two groups. Benefit from tobramycin is therefore short-lived and may reflect short-term changes in the faecal flora.

Bile reflux and intestinal metaplasia in gastric mucosa.

AIM: To determine associations between enterogastric bile reflux and gastric mucosal pathology. METHOD: A retrospective study using fasting gastric juice bile acid measurements and antral or prestomal biopsy specimens from 350 patients, 66 of whom had previously undergone surgery that either bypassed or disrupted the pyloric sphincter. RESULTS: Bile reflux was positively associated with reactive gastritis and negatively with Helicobacter pylori density. After stratification for previous surgery, age, and H pylori status, the histological feature most strongly associated with bile reflux was intestinal metaplasia, including all its subtypes. The prevalence of intestinal metaplasia was greatest in patients with both H pylori infection and high bile acid concentrations. Bile reflux was also positively associated with the severity of glandular atrophy, chronic inflammation, lamina propria oedema and foveolar hyperplasia. CONCLUSIONS: Bile reflux is a cause of reactive gastritis. It modifies the features of H pylori associated chronic gastritis. The changes are not confined to patients who have had surgery to their stomachs. The positive associations with atrophy and intestinal metaplasia have implications for models of gastric carcinogenesis.

High gastric juice ascorbic acid concentrations in members of a gastric cancer family.

Gastric juice ascorbic acid, total vitamin C, nitrite and N-nitroso-compound concentrations were determined in fasting gastric juice from four second generation members of a gastric cancer family, all of whom had Helicobacter pylori-associated chronic gastritis and intestinal metaplasia. Juice pH, nitrite and N-nitroso-compound concentrations were low. Juice ascorbate levels were comparable to those found in subjects with normal histology. The findings are contrary to our previous experience with juice ascorbate in H. pylori gastritis.

Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations.

The symptomatology of a case of acute infection with Helicobacter pylori is described, together with the accompanying changes in gastric mucosal histology, local and systemic humoral immune response, and gastric ascorbic acid concentration. The patient was an endoscopist, previously negative for the carbon-14 urea breath test, who had a week of epigastric pain and then became asymptomatic. H pylori was detected by culture of antral biopsy specimens and was still present after 74 days. Five days after infection the histological findings showed acute neutrophilic gastritis; by day 74 changes of chronic gastritis were evident. The patient seroconverted by IgG enzyme linked immunosorbent assay by day 74, but a mucosal IgM and IgA response was evident as early as day 14. Infection was accompanied by a transient hypochlorhydria but a sustained fall in gastric juice ascorbic acid concentration.

Screening dyspepsia by serology to Helicobacter pylori.

Owing to limited endoscopy resources, various screening strategies for endoscopy have been proposed. Helicobacter pylori can be detected with high sensitivity and specificity by serology, and therefore we assessed the effects on diagnostic accuracy and endoscopic workload of a policy of screening clinic patients with dyspepsia before endoscopy by a strategy based on age, Helicobacter pylori serology, and use of non-steroidal anti-inflammatory drugs. 1153 patients were studied, of whom 842 were of known histological H pylori status (histology group) and 293 had serum assessed prospectively by in-house and commercial ELISAs for detection of IgG antibodies to H pylori. Overall, the screening strategy would have reduced endoscopy workload by 23.3% (95% confidence interval 20.9-25.8%) and would have had a sensitivity for detection of peptic ulcer of 97.4% (94.5-99.1%). No peptic ulcer or malignant disease was missed in the patients studied prospectively, but 6 of 192 peptic ulcers in the histology group would have been missed. A policy of screening young dyspeptic patients for H pylori by serology is more sensitive than symptom-based screening strategies, and may have an important role in reducing endoscopy workload.

Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid and total bile acids in gastric juice of patients with and without precancerous conditions of the stomach.

To determine the relevance of gastric juice factors to gastric carcinogenesis, 56 patients with unoperated stomachs undergoing endoscopy for dyspepsia had gastric juice aspirated and analysed for pH, ascorbic acid, total bile acids, nitrite, nitrate and total nitroso compounds (NOCs). Plasma was obtained for vitamin C estimation. Antral and body biopsies were assessed for gastritis, Helicobacter pylori, atrophy and intestinal metaplasia (IM). Patients with chronic atrophic gastritis (n = 17) had lower gastric juice ascorbic acid concentrations (P less than 0.001), higher pH (P less than 0.05) and higher incidence of H. pylori infection (P less than 0.001) than normal subjects (n = 12). Patients with reflux gastritis (n = 9) had higher total bile acids (P less than 0.01). Patients with chronic gastritis and IM (n = 11) had higher gastric juice pH (P less than 0.01) and total bile acid concentrations (P less than 0.05), and lower gastric ascorbic acid concentrations (P less than 0.01) than those with chronic gastritis and no IM (n = 24). In chronic gastritis, high nitrite concentrations were associated with high pH (P less than 0.01). However, there were no significant differences in plasma vitamin C or gastric nitrite, nitrate or total NOC concentrations in relation to gastric histology. We conclude that the premalignant condition IM is associated with H. pylori infection, low gastric ascorbic acid levels and elevated total bile acids, but not to elevation in nitrite or total NOCs in fasting gastric juice.

Gastric juice ascorbic acid: effects of disease and implications for gastric carcinogenesis.

N-nitroso compounds (NOC) are strongly implicated in the causation of cancer of the stomach and it has been suggested that ascorbic acid might reduce the risk of gastric cancer by preventing their formation within gastric juice. However, until recently there have been no measurements of gastric juice ascorbic acid concentrations. We have measured both gastric juice ascorbic and total vitamin C (ascorbic acid and dehydroascorbic acid). Our findings suggest that ascorbic acid is secreted into the gastric lumen so that gastric juice concentrations are often greater than those in plasma. Gastric pathology affects this secretion, leading to values in gastric juice that are lower than plasma levels. Stimulation of gastric secretion does not raise vitamin C concentrations in individuals whose values are initially low. The role of ascorbic acid in preventing formation of NOC and protecting against gastric cancer is discussed in the light of these findings.

Gastric epithelium in the duodenum: its association with Helicobacter pylori and inflammation.

Duodenal biopsy specimens from 471 adults and 47 children were examined to determine the prevalence and distribution of gastric epithelium in the duodenal bulb in relation to age, gender, gastroduodenal inflammation, smoking, alcohol and consumption of nonsteroidal anti-inflammatory drugs (NSAID). Gastric metaplasia was present in the anterior wall duodenal biopsy specimen in 31%, was significantly less common in patients under 17 than in adults, and was more common in males than females. In sixty two adults who underwent multiple radial duodenal biopsy gastric metaplasia was randomly distributed around the duodenal circumference; sixty three per cent of the patients with gastric metaplasia found on multiple biopsy were detected by just the anterior biopsy. Gastric metaplasia was not obviously associated with alcohol, cigarette, or NSAID consumption. While the presence of gastric metaplasia was associated with adulthood, male sex, and low fasting gastric juice pH, its extent was associated with active duodenitis and Helicobacter-associated gastritis. On logistic regression, gastric metaplasia in the duodenum and gastric Helicobacter pylori were independent predictors of active duodenitis, but were not significantly associated with inactive duodenal inflammation. H pylori was observed in duodenal biopsy specimens from 32 patients, all with active duodenitis; bacteria were present only on foci of gastric metaplasia, and were more likely to be seen when the metaplasia was extensive. It is proposed that inflammatory injury to the duodenal mucosa by H pylori may stimulate the development of further gastric metaplasia, and that the area of duodenum susceptible to colonisation with H pylori may therefore increase progressively until mucosal integrity is compromised and ulceration supervenes.