Pathogenesis Of Duodenal Ulcer Research Articles

H. pylori in the pathogenesis of duodenal ulcer: interaction between duodenal acid load, bile, and H. pylori

OBJECTIVE: Helicobacter pylori (H. pylori) growth is inhibited by bile yet it can grow in the duodenal bulb and cause ulcer disease. The aim of this study was to test the effect of bile on H. pylori viability and growth and to determine whether acidification of bile reduces its inhibitory activity. METHODS: Fresh human bile was collected at laparotomy and tested for inhibitory activity of H. pylori using broth dilution assays. Six clinical isolates of H. pylori obtained from patients with duodenal ulcer were used for each experiment. The bile was diluted from 1:3 to 1:192; its inhibitory effect on H. pylori was tested before and after acidification, treatment with cholestyramine, or chloroform. Bile was acidified to a pH of 2–6, centrifuged at 8000 rpm for 20 min to remove precipitated bile acids, and the supernatant pH readjusted. Controls included BHI broth without bile (positive control) and bile that was acidified to pH 2 and neutralized without centrifugation. RESULTS: Human bile inhibited H. pylori growth in a dose dependent manner. Growth of all strains was supported for all strains only at a dilution of 1:192. In contrast, after acidification to pH ≤5 and centrifugation to remove precipitated bile acids, all strains grew at a bile dilution of 1:12. Neither chloroform extraction of lipids, nor acidification without centrifugation removed the inhibitory action of bile. In contrast, cholestyramine sequestration of bile acids completely removed all inhibitory activity. CONCLUSIONS: The duodenal acid load may be the critical factor to explain the ability of H. pylori to colonize the duodenal bulb by precipitating glycine-conjugated bile salts. The combination of a high duodenal acid load and H. pylori infection is likely the critical event in the pathogenesis of H. pylori-related duodenal ulcer disease.

H. pylori in the pathogenesis of duodenal ulcer: interaction between duodenal acid load, bile, and H. pylori.

Helicobacter pylori (H. pylori) growth is inhibited by bile yet it can grow in the duodenal bulb and cause ulcer disease. The aim of this study was to test the effect of bile on H. pylori viability and growth and to determine whether acidification of bile reduces its inhibitory activity. Fresh human bile was collected at laparotomy and tested for inhibitory activity of H. pylori using broth dilution assays. Six clinical isolates of H. pylori obtained from patients with duodenal ulcer were used for each experiment. The bile was diluted from 1:3 to 1:192; its inhibitory effect on H. pylori was tested before and after acidification, treatment with cholestyramine, or chloroform. Bile was acidified to a pH of 2-6, centrifuged at 8000 rpm for 20 min to remove precipitated bile acids, and the supernatant pH readjusted. Controls included BHI broth without bile (positive control) and bile that was acidified to pH 2 and neutralized without centrifugation. Human bile inhibited H. pylori growth in a dose dependent manner. Growth of all strains was supported for all strains only at a dilution of 1:192. In contrast, after acidification to pH < or =5 and centrifugation to remove precipitated bile acids, all strains grew at a bile dilution of 1:12. Neither chloroform extraction of lipids, nor acidification without centrifugation removed the inhibitory action of bile. In contrast, cholestyramine sequestration of bile acids completely removed all inhibitory activity. The duodenal acid load may be the critical factor to explain the ability of H. pylori to colonize the duodenal bulb by precipitating glycine-conjugated bile salts. The combination of a high duodenal acid load and H. pylori infection is likely the critical event in the pathogenesis of H. pylori-related duodenal ulcer disease.

The role of the host versus the environment in duodenal ulcer disease

Gastric functions can be understood only in the context of a network including the brain gut axis, neuro-endocrine and paracrine mechanisms and growth factors. These host factors including parietal cell sensitivity (PCS) may well interact with an important environmental factor, Helicobacter pylori (Hp), and help to explain its actions. The aim of this study was to investigate PCS related to Hp status and duodenal ulcer (DU). PCS was assessed by constructing dose-response curves after pentagastrin and calculating the D 50. Five groups of patients were studied: I) active DU, Hp pos. (8); II) history of DU, Hp pos. (8); III) asymptomatic Hp pos. (8); IV) asymptomatic Hp neg. (10); V) DU on maintenance H 2 blocker therapy, Hp pos. (20). PCS was repeated after Hp eradication. PCS was lowest in group IV, and in Hp pos. groups, was significantly higher, with insignificant differences among them, irrespective of DU. PCS declined significantly after Hp eradication. Group V showed an insignificant decline in PCS during treatment, not preventing recurrence. A higher PCS in Hp infection irrespective of DU, declining after eradication, suggests that this may be a reversible epiphenomena related to Hp infection. This may offer an explanation as to why DU develops only in some subjects with Hp, suggesting the importance of the host in the pathogenesis of DU.

Increased expression of IL-10 and IL-12 (p40) mRNA in Helicobacter pylori infected gastric mucosa: relation to bacterial cag status and peptic ulceration.

AIMS: To investigate interleukin (IL)-12 (p40) and IL-10 mRNA expression levels in the gastric mucosa in relation to H pylori cag status, peptic ulceration, and histopathology. METHODS: In 81 dyspeptic...

Oxidant stress, anti-oxidants, nitric oxide and essential fatty acids in peptic ulcer disease

In patients with duodenal ulcer (DU), the plasma levels of nitrite and lipid peroxides, the anti-oxidant content of red cells and plasma phospholipid fatty acid analysis were performed both before and after healing of the ulcer following treatment with lansoprazole, a proton pump inhibitor. These results showed that during the phase of active DU, the concentrations of antioxidants (superoxide dismutase, SOD, catalase and glutathione peroxidase) in red cells were low where as those of lipid peroxides and nitric oxide were high. Of the fatty acids measured, the concentration of palmitic acid (16:0) was increased during the active ulcer phase whereas those of arachidonic acid, alpha-linolenic acid and docosahexaenoic acid were low. These biochemical abnormalities reverted to normal following healing of the ulcer with lansoprazole. These results coupled with the observation that polyunsaturated fatty acids (PUFAs) can inhibit the growth of Helicobacter pylori and heal the ulcer suggest that free radicals, anti-oxidants, nitric oxide and PUFAs may play a significant role in the pathogenesis of DU. If this is true, it suggests that PUFAs can be exploited as potential anti-peptic ulcer drugs.

Helicobacter pylori Infection and the Pathogenesis of Duodenal Ulceration

Helicobacter pylori is a gram-negative spiral bacterium confined to the habitat of gastric-type epithelium. H. pylori causes duodenal ulceration by a cumulative effect of antral predominant gastritis with increased acid secretion, consequent gastric metaplasia in the duodenum (a site of further colonization by H. pylori), duodenitis, reduced duodenal bicarbonate secretion, and mucosal damage. Bacterial factors influence outcome. Major determinants are the production of a vacuolating toxin and the presence of CagA, an immunodominant product of a nonconserved gene cagA, a marker for the cag pathogenicity island that encodes virulence genes involved in induction of epithelial chemokine responses. In ulcer patients the mucosal immune response is polarized to a T-helper-1 (Th1) cell-mediated response, which may contribute to mucosal damage. Eradication of H. pylori restores acid output to normal. Loss of both acid and bacteria halts gastroduodenitis and allows ulcer healing. Gastric metaplasia does not regress in the short term.

Hans Selye and the development of the stress concept. Special reference to gastroduodenal ulcerogenesis.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.

The association between antral G and D cells and mucosal inflammation, atrophy, and Helicobacter pylori infection in subjects with normal mucosa, chronic gastritis, and duodenal ulcer.

The aim of this study was to clarify the mechanism of inappropriate hypergastrinemia in Helicobacter pylori (H. pylori)-infected subjects. We measured fasting serum gastrin (SG) concentrations, and investigated immunohistochemically G and D cell numbers in 47 subjects with normal mucosa, 24 subjects with chronic gastritis, and 24 subjects with duodenal ulcer (DU). The degree of inflammation and atrophy were classified into four categories based on criteria established in the Sydney System: none, mild, moderate, and severe. Avidin-biotin complex methods were used to identify G and D cells, which were counted per unit square (0.25 mm2) in five random fields from each of two well-oriented antral and fundic biopsies. SG concentrations were measured by radioimmunoassay. The G cell number was not significantly different between 24 subjects with H. pylori-associated gastritis and those with DU. However, the number of antral D cells was significantly lower and the G/D cell ratio was significantly higher in subjects with DU than in those with H. pylori-associated gastritis (p < 0.01), although the degree of inflammation and atrophy in the antrum and H. pylori status were similar between the two groups. The mean fasting SG concentration was higher in subjects with DU than in those with H. pylori-associated gastritis, but the difference was not statistically significant. Our results demonstrate that a marked decrease in antral D cell number with a high G/D cell ratio may contribute to hypergastrinemia and the pathogenesis of DU.

The association between antral G and D cells and mucosal inflammation, atrophy, and Helicobacter pylori infection in subjects with normal mucosa, chronic gastritis, and duodenal ulcer

Objective: The aim of this study was to clarify the mechanism of inappropriate hypergastrinemia in Helicobacter pylori ( H. pylori)-infected subjects. Methods: We measured fasting serum gastrin (SG) concentrations, and investigated immunohistochemically G and D cell numbers in 47 subjects with normal mucosa, 24 subjects with chronic gastritis, and 24 subjects with duodenal ulcer (DU). The degree of inflammation and atrophy were classified into four categories based on criteria established in the Sydney System: none, mild, moderate, and severe. Avidin-biotin complex methods were used to identify G and D cells, which were counted per unit square (0.25 mm 2) in five random fields from each of two well-oriented antral and fundic biopsies. SG concentrations were measured by radioimmunoassay. Results: The G cell number was not significantly different between 24 subjects with H. pylori-associated gastritis and those with DU. However, the number of antral D cells was significantly lower and the G/D cell ratio was significantly higher in subjects with DU than in those with H. pylori-associated gastritis ( p < 0.01), although the degree of inflammation and atrophy in the antrum and H. pylori status were similar between the two groups. The mean fasting SG concentration was higher in subjects with DU than in those with H. pylori-associated gastritis, but the difference was not statistically significant. Conclusions: Our results demonstrate that a marked decrease in antral D cell number with a high G/D cell ratio may contribute to hypergastrinemia and the pathogenesis of DU.

The role of life event stress in the pathogenesis of duodenal ulcer

The role of life event stress in the pathogenesis of duodenal ulcer

The role of life event stress in the pathogenesis of duodenal ulcer

The role of life events in the development of duodenal ulcer was examined. Patients with duodenal ulcer and with functional dyspepsia completed a modified version of the Social Readjustment Rating Scale, ticking the events experienced within the last 6 months. This was done just before the gastroscopy on which diagnoses were based. Neither in total life change score nor in perceived stress were significant differences between groups observed. In one category of events ulcer patients had even lower values than the controls. Our results do not support the widely held notion that stressful life events trigger onset or relapse of duodenal ulcer. © 1998 John Wiley & Sons, Ltd.

The role of nitric oxide in the pathogenesis of duodenal ulcer induced by cysteamine in rats

The role of nitric oxide in the pathogenesis of duodenal ulcer induced by cysteamine in rats

A marked high response of serum gastrin concentrations to the test meal may contribute to the pathogenesis of duodenal ulcer

Recent studies have indicated that Helicobacter pylori (17-1. py!ori) infection is associated with duodenal ulcer (DU). However, most of H. pylori-infected subjects do not develop DU. The AIM of this study was to clarify the pathogenesis of DU though investigating the meal-stimulated serum gastrin response in asymptomatic volunteers with or without tl. pylori infection and DU subjects. S_UBJECTS AND METHODS: The study population consisted of 31 H. pylori negative volunteers (27 males, mean age 26 yrs), 10 H. pylori positive volunteers (6 males, mean age 29 yrs), and 15 subjects with DU (13 males, mean age 29 yrs). After an overnight fast, blood samples were taken before and 15, 30, and 60 min after eating the test meal, which consisted of 100g rice, 130g chicken, and 1 egg (374 Kcal, 37.5 g carbohydrate, 41.5 g protein, and 11.6 g fat). The H. pylori infection status was determined by histology, serology, and the 13C-urea breath test. Serum gastrin concentrations were measured by radioimmunoassay. RESULTS: Results were expressed as the mean -+ standard error.

IL1 β gene Allele 2 involves the decreased production of gastric mucosal IL1β in response to Helicobacter pylori of common genetic strain in Japan, and relates to the pathogenesis of duodenal ulcer

IL1 β gene Allele 2 involves the decreased production of gastric mucosal IL1β in response to Helicobacter pylori of common genetic strain in Japan, and relates to the pathogenesis of duodenal ulcer

Role of active oxygen species and lipid peroxidation in mepirizole-induced duodenal ulcers in rats.

The role of active oxygen species and lipid peroxidation in the pathogenesis of duodenal ulcers induced by mepirizole was investigated in rats. Oral administration of mepirizole (200 mg/kg) resulted in ulcer lesions in the proximal duodenum. Thiobarbituric acid-reactive substances (TBA-reactive substances), an indicator of lipid peroxidation, also significantly increased in the duodenal mucosa. Myeloperoxidase (MPO) activity in the duodenal mucosa, a sign of polymorphonuclear leukocyte (PMN) accumulation, significantly increased. Combination treatment with polyethylene glycol-modified Serratia Mn-SOD and catalase significantly decreased the size of the ulcers and TBA-reactive substances in the duodenal mucosa. Allopurinol, a xanthine oxidase inhibitor, also reduced the size of duodenal ulcers. Both the size of the ulcers and the increase in TBA-reactive substances in the duodenal mucosa were significantly lower in PMN-depleted rats. Mepirizole increased the surface expression of adhesion molecule CD18 on PMNs in vitro. These results suggest that lipid peroxidation, mediated by active oxygen species generated from xanthine oxidase and PMNs, plays an important role in the pathogenesis of duodenal ulcers induced by mepirizole.

Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: A model

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Relationship between the mucosal production of reactive oxygen radicals and density of Helicobacter pylori in patients with duodenal ulcer.

To investigate the associations between the mucosal production of reactive oxygen radicals (RORs) in the gastric antrum and duodenum, Helicobacter pylori density and duodenal ulcer (DU). Forty-seven endoscoped patients, comprising 22 with DU and 25 non-ulcer subjects, were included in the study. Antral and duodenal biopsies were taken for histology, Helicobacter pylori culture and measurement of chemiluminescence. Biopsies were homogenized and cultured on Columbia blood agar plate. Colonies of H. pylori were counted and bacterial density expressed as colony-forming units (cfu)/mg of biopsy. Chemiluminescence was measured by luminometry and the results expressed as millivolt (mV)/min/mg of biopsy, after subtraction of background count. Thirty-one of 47 (66%) patients had antral H. pylori and 6/47 (12.8%) had proven duodenal colonization. Increased chemiluminescence (median (interquartile)) was found in H. pylori-infected patients compared to those without H. pylori in antral (90.0 (26.0, 249.0) vs. 7.0 (0.0, 10.0), P<0.001) and duodenal mucosa (22.0 (10.0, 100.0) vs. -2.5 (-10.0, 0.0) P<0.001). A positive correlation was found between antral H. pylori density and chemiluminescence response in both the antrum (r=0.77) and duodenum (r=0.52). DU patients showed an increased chemiluminescence compared to those non-ulcer subjects with or without H. pylori infection in antrum (163.5 (44.5, 297.8) vs. 33.0 (8.7, 168.0) (P=0.046) vs. 2.7 (0.1, 10.0), P<0.01) and duodenum (45.0 (17.5, 100.0) vs. 15.0 (-1.25, 22.5) vs. -2.5 (-10, 0.0), P<0.01). Increased production of RORs in the antrum and duodenum was found to be related to antral H. pylori density and associated with duodenal ulceration. The association between antral H. pylori and ROR release in the duodenum may be important in the pathogenesis of duodenal ulceration.

The role of blood flow in chronic duodenal ulcer.

Changes in gastroduodenal blood flow have been implicated in the pathogenesis of duodenal ulcer. We have studied duodenal blood flow during the development of an acute to chronic duodenal ulcer by using the abscopal model, in which ulcers are generated as an indirect effect of lower mediastinal irradiation. Female CFLP mice (n = 108) weighing 25-40 g were randomly allocated to one of three groups. Controls were not irradiated. Irradiated 'controls' received 18 Gy 250 kV X-rays to the upper mediastinum (which does not cause duodenal ulceration). The lower mediastinum group received the same dose of irradiation, which has been shown to induce typical chronic duodenal ulcers in 45% of animals so treated. Animals were studied by means of radiolabelled microspheres 3 or 7 days later (that is, during and at the end of the lag period for ulcer induction). Proximal duodenal blood flow specifically was reduced by 32% in the lower mediastinum group compared with irradiated controls at 7 days (4.3 versus 6.3 ml/g tissue/min; P = 0.025 by ANOVA with contrast); there was no significant difference in blood flow to the stomach and to the distal duodenum. The decrease in proximal duodenal blood flow in the lower mediastinum group did not differ in the five animals that developed ulcer compared with the seven that did not. Although there is an overall decrease in duodenal blood flow associated with chronic duodenal ulcer, reduced blood flow may not explain individual susceptibility to ulceration.

Peptic ulcer pathogenesis

In the absence of non-steroidal anti-inflammatory drugs pathogenesis of peptic ulceration is multifactorial with Helicobacter pylori and gastric acid as equally the most important and the most likely steps in a cascade of events, starting with H. pylori infection during childhood and resulting in the outbreak of the disease years to decades later. One important cofactor in the pathogenesis of duodenal ulceration is gastric metaplasia, with gastric acid as predisposing factor and H. pylori as modulator of size and of the extent of inflammation. There has been considerable progress in our understanding of how H. pylori contributes to the well known gastric acid hypersecretion, to basal and postprandial hypergastrinaemia, to the severity of inflammation of antral metaplasia in the duodenal bulb, and thus to the predisposition for ulcer formation.

Helicobacter pylori and Gastroduodenal Disease.

Helicobacter pylori is a gram negative spiral bacterium, which is colonized in human gastric mucosa. This organism was first reported in Australia, 1983. Now H. pylori has been recognized to cause chronic active gastritis, and is a major factor in the pathogenesis of duodenal ulcer and gastric ulcer. It was also reported that its infection is a risk factor for both MALT (mucosa associated lymphoid tissue) lymphoma and gastric adenocarcinoma. H. pylori has many virulence factors. Urease is one of the most important colonization and virulence factors studied. Ammonia made by urease protects the organisms from gastric low pH, and is toxigenic to gastric epithelial cells. Vacuolating toxin and CagA proteins are thought to be pathogenic agents especially for causing gastric and duodenal ulcers. Neutrophil reactions against the bacteria, and the abnormal immunological reactions are also considered to cause the damage of gastric epithelial cells, although the detailed pathogenic mechanisms are still not clear. In developing countries, infection by H. pylori is established in childhood, and the organisms can be identified in the mouth and feces, indicating its infection through water. The infected organisms can be eradicated by administration with proton pump inhibitor and one or two antibiotics. This may provide an useful therapeutic means to the patients especially with recurrent ulceration and MALT lymphoma.