Mucosal cell proliferation in duodenal ulcer and duodenitis.

Mucosal cell proliferation in the first part of the duodenum was studied in 24 patients using a tissue culture technique in which endoscopic biopsies were subjected to autoradiography after exposure to tritiated thymidine. Eight patients had a normal duodenum, eight had duodenal ulcer, and eight had symptomatic chronic non-specific duodenitis. The mean crypt labelling index (LI) in normal duodenum was 8.8 0.4% (SEM). Increased labelling indices of 15.6 +/- 1.7% were found near the edge of duodenal ulcers and 17.8 1.8% in duodenitis. Treatment with cimetidine reduced both the severity of duodenitis and the mean crypt LI. The LI of histologically normal duodenal mucosa distal to ulcer of duodenitis was similar to that of the control subjects' mucosa. The increased mucosal cell proliferation seen in severe duodenitis, either alone or associated with duodenal ulceration, suggested that erosions and ulcers arose when the crypts passed into 'high output failure' and were unable to compensate for further epithelial cell loss. There was no evidence in out study for a generalised failure of mucosal cell proliferation in duodenal ulcer or duodenitis.     

Epithelial cell proliferation in duodenal ulcer

Epithelial cell proliferation in the duodenum was investigated in 50 patients by incubating mucosal biopsy samples with tritiated thymidine, followed by autoradiography. Fifteen patients had a normal duodenum, 15 duodenal ulcer undergoing elective surgery, 10 perforated duodenal ulcer, and 5 severe non-ulcer-associated duodenitis. The mean crypt cell labelling index in the duodenal bulb of controls was 8.8 +/- 0.4% (mean +/- SEM), at the edge of perforated ulcers 19.1 +/- 2.0%, at the edge of elective ulcers 18.6 +/- 1.4%, and in biopsy specimens from non-ulcer-associated duodenitis 14.0 +/- 1.2%. The mean labelling index in the distal first part of duodenum of control patients was 9.1 +/- 0.8 similar to the values found in histologically normal specimens distal to ulcer or duodenitis. The results indicate active epithelial cell proliferation in both duodenal ulcer and duodenitis. There was no evidence of impairment of epithelial cell proliferation in duodenal ulcer patients.     

Epithelial Cell Proliferation in Duodenal Ulcer

Epithelial cell proliferation in the duodenum was investigated in 50 patients by incubating mucosal biopsy samples with tritiated thymidine, followed by autoradiography. Fifteen patients had a normal duodenum, 15 duodenal ulcer undergoing elective surgery, 10 perforated duodenal ulcer, and 5 severe non-ulcer-associated duodenitis. The mean crypt cell labelling index in the duodenal bulb of controls was 8.8 ± 0.4% (mean ± SEM), at the edge of perforated ulcers 19.1 ± 2.0%, at the edge of elective ulcers 18.6 ± 1.4%, and in biopsy specimens from non-ulcer-associated duodenitis 14.0 ± 1.2%. The mean labelling index in the distal first part of duodenum of control patients was 9.1 ± 0.8 similar to the values found in histologically normal specimens distal to ulcer or duodenitis. The results indicate active epithelial cell proliferation in both duodenal ulcer and duodenitis. There was no evidence of impairment of epithelial cell proliferation in duodenal ulcer patients.     

Somatostatin in rat tissues is depleted by cysteamine administration

Administration of cysteamine (mercaptoethylamine) induces in rats severe perforating duodenal ulcers. Because the ulcerogenic properties of cysteamine are markedly reduced by treatment with somatostatin, we considered the possibility that cysteamine-induced duodenal ulcer might be mediated by depletion of tissue somatostatin, and thereby of its paracrine influences on gastrin and gastric acid secretion. To test this hypothesis, we measured the concentration of immunoreactive somatostatin (IR-somatostatin) in stomach and duodenal mucosa at intervals after administration of a single ulcerogenic dose (30 mg/kg by stomach tube). IR-somatostatin in these tissues fell rapidly to reach a minimum at 4 h (stomach 31%, duodenum 60% of control respectively). IR-somatostatin in hypothalamus and pancreas decreased gradually to a minimum at 7 h. Another duodenal ulcerogen, propionitrile (10 mg/100 g bw, s.c.) which is more toxic than cysteamine, and several stressful procedures including ether anesthesia, restraint and s.c. formalin did not lower stomach or duodenal IR-somatostatin. Gut, pancreas and hypothalamic VIP levels were not influenced by cysteamine. These findings suggest that cysteamine is a relatively specific depletor of tissue somatostatin. Because blood levels of somatostatin fell, and only trivial amounts of the peptide were found in the stomach lumen after cysteamine administration, it appears likely that this agent acts at the cellular level to cause breakdown of preformed somatostatin and/or to acutely reduce its synthesis.     

Effect of ranitidine on gastric and duodenal mucosal enzyme activities in duodenal ulcer patients

The activities of 11 marker enzymes from the gastric and duodenal mucosa were determined in 19 patients with active duodenal ulcer disease (DU) before therapy, after 4 weeks of therapy with ranitidine, 300 mg/day, and after another 4 weeks without treatment. The activities were measured in homogenized material obtained with forceps through an endoscope. The healing rate at 4 weeks was 68%. In the descending duodenum the activities of the membrane enzymes increased during the treatment period compared with pre-treatment activities. Although not as extensive as in the descending duodenum, an increase of membrane enzyme activities was also noted in the duodenal bulb during treatment. In the gastric mucosa only minor enzymic activity changes were seen. The altered enzyme activities in duodenum and stomach during treatment were independent of ulcer healing, smoking, antacids, and mucosal inflammation. Previously, significant differences in mucosal enzyme activities have been demonstrated between DU patients and controls. During ranitidine treatment the enzyme activities in the duodenal mucosa of the same DU patients tended to normalize, whereas they were mostly unchanged in the gastric mucosa. Four weeks after treatment the mucosal enzyme activities in the duodenum were as before treatment started, without occurrence of ulcer relapse. The altered enzymic activities of the duodenal mucosa in DU patients therefore seem to be largely independent of the presence of active ulcer.     

Relationship between tissue calcium content and duodenal ulcer in the rat

Since the effect of cellular calcium on cell injury has been in question, this study focused on the relationship between tissue calcium content and cysteamine-induced duodenal ulcer. Rats treated with cysteamine showed a high frequency and severity of duodenal ulcer, and the calcium content in the duodenal mucosa was elevated. Furthermore, the level of calcium content in duodenal mucosa was positively associated with the severity of the duodenal lesion. Whereas administration of calcium increased duodenal ulcerative response to cysteamine, verapamil afforded protection against ulceration. We conclude that calcium accumulation in duodenal mucosa is related to duodenal ulceration induced by cysteamine.     

Cysteamine-induced inhibition of acid neutralization and the increase in hydrogen ion back-diffusion in duodenal mucosa

To investigate the possible impairment of defensive mechanisms in cysteamine-induced duodenal ulceration, the effect of cysteamine on the neutralization of acid by the duodenum and the back-diffusion of hydrogen ions into the duodenal mucosa has been studied. The results obtained were as follows. (1) The intraduodenal pH started to decrease between 3 and 4 hr after cysteamine injection. (2) By perfusion of the duodenal loop excluding the opening of bile and pancreatic ducts, the amount of hydrogen ions (H⁺) neutralized was found to be significantly lower in cysteamine-treated animals than in the controls. (3) the back-diffusion of luminal H⁺ into the duodenal mucosa, estimated by measuring the H⁺ disappearance from the test solution including 100 mM HCl, was significantly increased by cysteamine. From these findings, it has been concluded that cysteamine reduces the resistance of duodenal mucosa to acid coming from the stomach.     

Altered Concentrations of Gastrin-Releasing Polypeptide and Somatostatin in Fundic and Duodenal Bulb Mucosa of Patients with Duodenal Ulcer Disease

The concentrations of gastrin-releasing polypeptide, somatostatin (SS), and gastrin in extracts of endoscopically obtained biopsies from the fundus, antrum, and duodenum of patients with uncomplicated bile stones (controls) or duodenal ulcer disease were measured with specific radioimmunoassays. The validity of the tissue sampling was confirmed by characteristic and significant differences between gastrin concentrations at the different biopsy sites. Gastrin-releasing polypeptide levels were at their highest in the fundic and duodenal bulb compared to the antrum in controls (p less than 0.01), whereas no differences in gastrin-releasing polypeptide content of the different parts of the stomach were found in duodenal ulcer patients. Compared to controls gastrin-releasing polypeptide in duodenal ulcer patients was reduced in fundic and duodenal bulb mucosa (p less than 0.01). SS levels were highest (p less than 0.05) in the first part of duodenum in controls. Compared to controls duodenal ulcer patients had lower SS concentrations present in fundic (p less than 0.01) and highest SS concentrations present in duodenal bulb mucosa (p less than 0.01). There was no correlation between acid secretion and mucosal gastrin-releasing polypeptide or SS concentrations in any part of the stomach and duodenum.     

Epidermal growth factor inhibits cysteamine-induced duodenal ulcers

The effect of the duodenal ulcerogen cysteamine on secretion of epidermal growth factor from Brunner's gland pouches was studied in the rat. Total output of immunoreactive epidermal growth factor was reduced to approximately 55%, compared with controls, 5 h after administration of cysteamine (300 mg/kg, s.c.). Furthermore, measurements on tissue extracts of the pouches revealed that 5 h after cysteamine treatment, Brunner's glands were depleted of epidermal growth factor. The effect on ulcer development of intraduodenally applied exogenous epidermal growth factor (1 micrograms/kg . h) also was studied. Luminal epidermal growth factor significantly inhibited the formation of cysteamine-induced duodenal ulcer, compared with controls receiving saline. The effect was not due to inhibition of gastric acid secretion or stimulation of duodenal bicarbonate secretion since the dose of epidermal growth factor used, when tested on chronic fistula rats, had no effect on acid secretion and did not influence bicarbonate secretion from Brunner's gland pouches. These results demonstrate that epidermal growth factor has a cytoprotective effect on the duodenal mucosa, and it is suggested that inhibition of synthesis and secretion of endogenous epidermal growth factor may be a pathogenetic factor in cysteamine-induced duodenal ulcer.     

Effect of gastric hypersecretion on the canine duodenum.

The neutralization of acid introduced into the duodenum has been found to be less intensive in patients with duodenal ulcer than in controls. The present work studied the possibility that chronic gastric hypersecretion injures the duodenal mucosa and thereby influences the neutralization system. Gastric hypersecretion was provoked for 3 weeks in 3 dogs by a daily injection of a gastrin preparation with prolonged effect. After a subcutaneous injection of this preparation given together with a test meal the acidity of both gastric and duodenal contents was found to increase significantly. After the 3 weeks of gastric hypersecretion the pancreatic bicarbonate response to exogenous secretin was unchanged, while the bicarbonate response to duodenal acidification was decreased from 2.03 mEq/30 min to 1.27 mEq/30 min (p less than 0.05), compatible with an impaired secretin release. Also the concentration of lactase, maltase, sucrase, and alkaline phosphatase in mucosal biopsies from the second part of the duodenum was significantly reduced (p less than 0.001). These results indicate that gastric hypersecretion causes mucosal damage in the duodenum and thereby reduces the release of secretin.     

Selective inhibition of duodenal and jejunal villous cell alkaline phosphatase by the duodenal ulcerogen cysteamine

We have found that cysteamine-HCl, a potent duodenal ulcerogen, after a single subcutaneous injection (30 mg/100 g body weight), inhibited villous cell duodenal and jejunal alkaline phosphatase (APase) under in vivo and under in vitro conditions. The duodenal and jejunal crypt-cell APase was not susceptible to cysteamine inhibition. Ileal APase from both the villous and the crypt cells was unaffected by cysteamine. Tissue-nonspecific APase from the kidney and liver was not affected by cysteamine either. The differences in tissue and cellular accumulation of cysteamine, the submolecular differences in APase molecules, and its anatomical localization in mucosal cells along the small intestine could explain the different degrees of susceptibility to cysteamine inhibition. The extent of duodenal APase inhibition by cysteamine was highly pH-dependent and varied from 5% to 85% within a pH range of 7.5-10.5. A shift in pH optimum from 9.6 to 9.3 was found in the presence of cysteamine. The inhibition of duodenal villous cell APase was greatly dependent on cysteamine concentration (Ki = 2.65 mM). At a fixed concentration of cysteamine it was not influenced by substrate concentration. Cysteamine did not change the Km value for duodenal APase but did decrease its Vmax to 46% and 15% of the controls when added in the assay or injected subcutaneously, respectively, indicating that the inhibition was of the linear, 'noncompetitive' type. Somehow cysteamine increased the requirement in the activation energy for substrate hydrolysis as well. The data indicate that macromolecular transformations could take place in the mucosal cells of duodenum after cysteamine administration.     

Healing process of duodenal ulcers induced by indomethacin plus histamine in rats

Healing of duodenal ulcers induced by indomethacin + histamine was investigated in rats. Animals were treated with indomethacin (5 mg/kg, s.c., once daily) and histamine (40 mg/kg, s.c., 3 times every 2.5 h after indomethacin treatment) for 2 days under fasting conditions, and they were fed normally thereafter. The duodenal ulcers so induced were confined to the proximal part of the duodenum and penetrated to the muscular mucosa with an incidence of over 80% when determined 32 h after the first injection of indomethacin (day 1). The ulcers became smaller and shallower within 7 days with granulation from the ulcer base, the mucosa grew in from the edges over the surface of granulation tissue, and they had healed almost completely after 15 days with epithelial regeneration from the edge of the ulcers. The healing of ulcers was significantly promoted by a 5-day treatment with an antacid (Al(OH)3) as well as antisecretory agents (omeprazole, cimetidine, propantheline bromide) and 16,16-dimethyl prostaglandin E2 at the dose which produced a potent inhibition of acid output and a marked increase in duodenal alkaline secretion. These results suggest that the duodenal ulcers induced in rats by indomethacin + histamine may provide a useful model for studying the healing process of duodenal ulcers and for the evaluation of the drugs with possible effects on ulcer healing.     

Effect of Cimetidine on Gastric Mucosal Cell Proliferation in Man

Seven duodenal ulcer patients were treated for 3 months with cimetidine. Before and after treatment endoscopic biopsy specimens were taken for autoradiographic estimation of cell proliferation in the gastric mucosa in the antral and fundic part of the stomach and from the duodenum. In all three areas the estimated labeling index was increased during medication with cimetidine. The increase in epithelial cell renewal may participate in the ulcer healing effect of cimetidine.     

Effect of cimetidine on gastric mucosal cell proliferation in man

Seven duodenal ulcer patients were treated for 3 months with cimetidine. Before and after treatment endoscopic biopsy specimens were taken for autoradiographic estimation of cell proliferation in the gastric mucosa in the antral and fundic part of the stomach and from the duodenum. In all three areas the estimated labeling index was increased during medication with cimetidine. The increase in epithelial cell renewal may participate in the ulcer healing effect of cimetidine.     

Link betweenHelicobacter pylori-associated gastritis and duodenal ulcer

We examined the interrelationships among the degree of fundic mucosal atrophy, the prevalence ofHelicobacter pylori in the gastric antrum, the gastric juice, and the duodenum with and without gastric metaplasia, in 20 duodenal ulcer patients and 20 non-duodenal ulcer patients. The detection rates ofH. pylori in the antrum, the gastric juice, and the duodenum were significantly higher in duodenal ulcer patients (80%, 65%, and 60%) than in non-duodenal ulcer subjects (50%, 20%, and 5%). The frequency ofH. pylori was significantly lower in the gastric juice (30%) and the duodenum (10%) in non-duodenal ulcer patients with antralH. pylori, compared with those in duodenal ulcer patients with antralH. pylori. All of seven patients with both gastric metaplasia andH. pylori infection in the duodenum had duodenal ulcer, whereas only 1 of 14 patients without either gastric metaplasia orH. pylori infection in the duodenum had duodenal ulcer. There was normal or mild atrophic mucosa in the fundus of duodenal ulcer patients withH. pylori in the antrum, whereas moderate or severe atrophic mucosa in non-duodenal ulcer patients withH. pylori gastritis. These results suggest that the preserved fundic mucosa, gastric metaplasia in the duodenum, and a greater load ofH. pylori to the duodenum through the gastric juice may be prerequisites for the formation of duodenal ulcers.     

Effect of cysteamine on gastric nerve fibers containing gastrin-releasing peptide in the rat

In rats, changes in gastric nerve fibers containing gastrin-releasing peptide (GRP) in cysteamine-induced duodenal ulcer were investigated in relation to the dynamics of gastrin-producing cells (G-cells). Marked increases in gastric acid secretion and serum gastrin level were observed from 2h after the administration of cysteamine. The number of G-cells was significantly decreased from 2h after the injection of cysteamine. Two and 4h after the administration of cysteamine, the G-cells showed ultrastructural changes characterized by a markedly decreased number of secretory granules. Circulating GRP levels were significantly elevated from 2h after the administration of cysteamine. In the control group given vehicle only, nerve fibers showing immunoreaction for GRP formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa, located close to capillaries and demonstrated varicosities that contained either small clear vesicles or GRP-immunopositive vesicles with large cores. Eight h after the administration of cysteamine, there was depleted GRP immunoreactivity, evidenced by a markedly decreased number of vesicles, with large electron-dense cores, in the oxyntic mucosa. These findings suggest that, in cysteamine-induced doudenal ulcer, alterations in gastric nerve fibers containing GRP may be related to hypergastrinemia.     

Gastric metaplasia and duodenal ulcer disease in children infected by Helicobacter pylori.

BACKGROUND--Helicobacter pylori infection of the gastric mucosa is vital in the pathogenesis of duodenal ulcer disease. H pylori will only colonise gastric epithelium and its association with duodenal disease is therefore not easily explained. AIMS--To determine if gastric metaplasia in the duodenum increases the risk of duodenal ulcer disease in children infected with H pylori. PATIENTS--All children undergoing upper endoscopy over a 20 month period in a children's hospital in Ireland. METHODS--Two biopsy specimens were obtained from the antral mucosa and two from the first part of the duodenum. One antral biopsy specimen was used in a rapid urease test (Clo Test). Biopsy sections were stained with haematoxylin and eosin and also with cresyl violet for identification of H pylori. Periodic acid Schiff (PAS) stain was performed to identify areas of gastric metaplasia. RESULTS--Gastric and duodenal biopsy specimens were obtained from 148 patients (M:F 1:2:1). Twenty five children (17%) had H pylori positive gastritis. Thirty four children (23%) had gastric metaplasia in the duodenum. Nine per cent of children under the age of 8 years had gastric metaplasia compared with 38% in those 12 years of age or over (p < 0.005). Seven children had duodenal ulcer disease. Gastric metaplasia was present in six of seven (86%) children with duodenal ulcer disease compared with 28 of 141 (20%) without ulceration (p < 0.001). While both H pylori and gastric metaplasia were each significant risk factors for duodenal ulcer disease, the combined presence of both factors was associated with a pronounced increase in duodenal ulcer disease. Duodenal ulcer disease occurred in over 50% of children with both H pylori infection and gastric metaplasia. In contrast duodenal disease did not occur in children (0 of 100) when both were absent. CONCLUSION--The presence of gastric metaplasia in the duodenum is the major risk factor for duodenal ulcer disease in patients colonised by H pylori.     

Helicobacter pylori and chronic active inflammation of the duodenum and stomach in duodenal ulcer patients treated with ranitidine, misoprostol, or an acid-neutralizing agent

Biopsy specimens from the stomach and duodenum of 45 duodenal ulcer patients treated with ranitidine, misoprostol, or an antacid were examined. During 4 weeks of treatment the duodenal ulcer healed in 31 patients. The treatment regimens showed no significant effect on the amount of Helicobacter-like structures (HLS) or the presence of active inflammation, either in the stomach or in the duodenum. All patients had chronic active antral gastritis before and after treatment. HLS were found histologically in 91.7% of all antral specimens, in 94.2% of the gastric corpus specimens, in 15.9% of the duodenal bulb specimens, and in 0.9% from the lower duodenal knee. The frequency of chronic active gastritis was clearly lower in the gastric corpus than in the antrum, whereas the occurrence of HLS was about the same. This may indicate a higher resistance of the gastric corpus mucosa to H. pylori.     

Effect of cysteamine on gastroduodenal mucosal histamine in rat

Cysteamine administration to rats is followed by a high incidence of peptic ulceration. The aim of the present study was to investigate the effect of cysteamine on gastric and duodenal mucosal histamine and gastric mucosal histamine formation capacity. After a four hour fast, cysteamine in doses of 50, 100, 200, 300, 400, and 500 mg/kg bodyweight was injected subcutaneously to male Wistar rats; saline injection was used as control. After 24 hours the animals were killed; the stomach and duodenum were removed and examined for ulceration. Mucosal biopsies were taken for histamine studies. Gastric and duodenal ulceration tended to appear with increasing incidence with higher doses. A direct correlation was found between the dose of cysteamine and gastric mucosal histamine (p less than 0.02), and duodenal mucosal histamine (p less than 0.05). Further, a direct relationship was found between gastric mucosal histidine decarboxylase activity and the dose of cysteamine (p less than 0.05). Gastric mucosal histamine and histidine decarboxylase activity showed a direct correlation (p less than 0.001). Gastric and duodenal mucosal histamine and gastric mucosal histamine formation capacity were higher in rats with ulcers than in controls and rats without ulcers. In rat, cysteamine induces dose related changes in mucosal histamine and histidine decarboxylase activity. These changes are related to ulcer formation; histamine may be involved in the pathophysiology of cysteamine induced ulcer formation.     

Non-steroidal anti-inflammatory drugs inhibit the processes of mucosal cell proliferation associated with duodenal ulcer healing.

We demonstrate that, in patients taking non-steroidal anti-inflammatory drugs (NSAIDs), there is inhibition of the proliferation of mucosal cells that normally leads to healing of duodenal ulcers. A microdissection technique was used to quantitate mitosis in duodenal crypts at the ulcer edge, giving a regeneration index of mitotic rate at that site, as compared to nearby mucosa. In patients with duodenal ulcers occurring in the absence of NSAID therapy, there was a brisk regenerative response (median index 2.48, range 1.55-9.81, n = 8), significantly greater than in patients taking NSAIDs (median index 1.10, range 0.73-2.16, n = 10, p = 0.014). Inhibition of the process of epithelial cell division normally involved in duodenal ulcer healing could contribute to the delay in ulcer healing which may explain the higher complication rate for duodenal ulcer during NSAID therapy.