Pathogenesis Of Duodenal Ulcer Disease Research Articles

Duodenal Acid Clearance in Humans: Observations Made with Intraluminal Impedance Recording

Duodenal acid clearance appears to be involved not only in the pathogenesis of duodenal ulcer disease but also in functional dyspepsia. Duodenal contractile activity can help to maintain neutral pH in the duodenum by mixing acid with bicarbonate or by aborally transporting the acid load. Intraluminal impedance recording, allowing the detection of nonacid liquid boluses, can be carried out concomitantly with antroduodenal manometry and pH recording and may thus provide useful information about the mechanisms involved in duodenal clearance of endogenous acid and volume boluses. Eight H. pylori-negative healthy volunteers were studied with two catheters positioned across the pylorus, allowing the recording of five impedance signals (one antral, one pyloric, and three duodenal) simultaneously with six pressure signals (two antral, one pyloric, and three duodenal) as well as distal antral and proximal duodenal pH. During phase II of the migrating motor complex, which is known to be associated with the highest duodenal acid exposure, each duodenal acidification event (defined as a pH drop >2 pH units) was characterized by its maximal amplitude, duration, temporal relationship with antroduodenal manometric events, and relation to impedance variations. Acid was considered to have been cleared from the duodenum when the preacidification pH was restored (+/-0.2 unit). A total of 164 duodenal pH drops were recorded during the 323 min of phase II recordings. Eleven percent of the duodenal acidification events were short-lived (<10 sec). All of these events were temporally associated with a propagated antroduodenal contraction and a short-lived drop in impedance, suggesting rapid aboral passage of the acid bolus. The long-lived duodenal acidification events lasted a mean of 32 sec (range, 25-66 sec). In 90% of these events an antroduodenal propagated contraction was recorded at the time of onset. Repetitive duodenal contractions followed the onset of the long-lived acidification events in 34% of the cases. These remained present until complete clearance of the acid. In 81% of the long-lived acidification events, recovery of the associated impedance drop occurred simultaneously with the pH recovery, suggesting a complete clearance of the bolus. Less frequently (19%), the duodenal pH recovered while the impedance remained low, suggesting that the bolus was not cleared but neutralized. Interdigestive duodenal acidification events usually last about 30 sec. They evoke duodenal contractions in only one-third of cases. Combined pH and impedance recording makes it possible to distinguish between neutralization of acid boluses and their complete total clearance.

The effect of the eradication of Helicobacter pylori infection on hemorrhage because of duodenal ulcer.

The cost of a recurrently bleeding duodenal ulcer (DU) is very high, both from a human and an economic point-of-view. Helicobacter pylori infection plays an important role in the pathogenesis of DU disease and its complications, such as bleeding. Cure of H. pylori infection is recommended in patients with DU and its complications, although in the latter case, the most efficient management is not yet a defined issue. In particular, acid secretion inhibitors may not contribute to long-term cure. Our aims were to ascertain whether the recurrence of bleeding because of DU could be prevented by H. pylori eradication and whether long-term inhibition of gastric acid output is needed to prevent recurrence. Eighty-four patients (65 men; mean age, 55.1 years), who had bled because of recurrent DU, were followed after the cure of H. pylori infection. None of the patients were on therapy with nonsteroidal antiinflammatory drugs. Successful cure of H. pylori was determined by gastroscopy, histology, and serology performed at 3, 6, 12, 24, and 48 months after the eradication treatment. A 13C urea breath test was performed when the results of serology were unclear and also at recurrence of DU or bleeding. After the antibiotic treatment, 46 patients stopped all medications, whereas 38 continued long-term therapy with histamine type 2 receptor antagonists. During a mean follow-up period of 47.2 months (range, 37-65 months), recurrence of DU at endoscopy was observed in three patients in each group (p = 0.56), but none bled again. We conclude that H. pylori eradication prevents DU recurrence and rebleeding, that reinfection rate by H. pylori after cure was nil at 4 years, and that long-term inhibition of acid secretion may not improve outcome after cure of H. pylori, even in patients whose DU was complicated by hemorrhage.

Pathogenesis of duodenal ulcer disease: the rest of the story

Although several duodenal ulcer disease-specific abnormalities in gastric function have been described (e.g. exaggerated gastrin releasing peptide-stimulated acid secretion and an abnormal sensitivity of the parietal cells to gastrin), none has withstood careful examination. We describe here the critical nature of the duodenal acid load in precipitating and washing out bile salts, which inhibit the growth of Helicobacter pylori(H. pylori) in the development of duodenal ulcer disease. The risk of duodenal ulcer is enhanced by infection with pro-inflammatory H. pylori(e.g. with an intact cag pathogenicity island). Progressive damage to the duodenum promotes gastric metaplasia, resulting in sites for H. pylori growth and more inflammation. This cycle results in an increasing inability of the duodenal bulb to neutralize acid entering from the stomach until changes in duodenal bulb structure and function are sufficient for an ulcer to develop. Cure of the H. pylori infection results in a sustained fall in duodenal acid load as well as a marked (and continuing) reduction in inflammation, which results in the cure of chronic ulcer disease.

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

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. To determine if gastric metaplasia in the duodenum increases the risk of duodenal ulcer disease in children infected with H pylori. All children undergoing upper endoscopy over a 20 month period in a children's hospital in Ireland. 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. 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. 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 disturbance of gastric function associated with duodenal ulcer disease and gastric cancer.

Helicobacter pylori is now recognized as the major acquired factor in the pathogenesis of duodenal ulcer disease (DU). There is also an association between H. pylori infection and the subsequent development of gastric cancer. The mechanisms by which such infection predisposes the host to these diseases are incompletely understood, but disorders induced by the bacterium in gastric function play a pivotal role. In most patients, H. pylori infection stimulates acid secretion, leading to a predisposition to DU development. However, in some patients, the infection is associated with a significant decrease in acid secretion, a predisposition to gastric cancer. These divergent effects of H. pylori on gastric acid secretion explain the early conflicting reports on changes in acid secretion associated with the infection. The reason why H. pylori infection produces divergent effects on gastric acid secretion is unclear, but may be related to differences in bacterial strains or genetic, dietary or other environmental factors.

Inhibition and stimulation of prolactin release. Delayed response in duodenal ulcer patients.

Prolactin inhibitory tests (bromocriptine in a single dose 2.5 mg orally) as well as stimulatory tests (metoclopramide in a single dose of 10 mg intravenously) were performed in 33 patients with endoscopically proven duodenal ulcer and in 32 healthy volunteers. Delayed response in inhibition of prolactin release as well as in stimulation of prolactin release was observed in duodenal ulcer patients compared to healthy volunteers (P < 0.01). The results implicate the role of the dopamine-prolactin axis in the pathogenesis of duodenal ulcer disease.

Herpes viruses and duodenal ulcer disease

Antibodies to herpes simplex virus and Epstein-Barr virus were sought in the sera of 33 patients with endoscopically proved duodenal ulcer and 33 healthy controls. Neither the prevalence nor the antibody levels to both viruses were significantly different between the two groups. These results suggest that herpes viruses may not play a role in the pathogenesis of duodenal ulcer disease.

Regulation of duodenal bicarbonate secretion during stress by corticotropin-releasing factor and beta-endorphin.

Proximal duodenal mucosal bicarbonate secretion is an important factor in the pathogenesis of duodenal ulcer disease. To examine the central nervous system regulation of duodenal bicarbonate secretion, an animal model was developed that allowed cerebroventricular and intravenous injections as well as collection of duodenal perfusates in awake, freely moving rats. The hypothalamic peptide corticotropin-releasing factor (CRF) and stress (physical restraint) significantly stimulated duodenal bicarbonate secretion. These responses were abolished by pretreatment of the animals with the CRF receptor antagonist alpha-helical CRF-(9-41), hypophysectomy, and naloxone. In contrast, blockade of autonomic efferents by surgical and pharmacological means did not prevent the stimulatory effects of stress and CRF. Intravenous, but not cerebroventricular, administration of beta-endorphin that produced plasma concentrations of beta-endorphin that were similar to those produced by exogenous CRF and stress significantly stimulated duodenal bicarbonate secretion. These results indicate that endogenous CRF released during stress and exogenously administered CRF stimulate duodenal bicarbonate secretion by release of beta-endorphin from the pituitary, thus, demonstrating a functional hypothalamus-pituitary-gut axis.

Histamine and duodenal ulceration in renal transplant recipients.

Six of 25 renal transplant recipients had a duodenal ulcer at endoscopy. Histamine concentration and the activity of histamine methyltransferase, the degrading enzyme of histamine, were measured in gastric mucosal biopsies obtained at endoscopy and compared with patients with duodenal ulcer but not undergoing transplant and with patients with an apparently normal stomach and duodenum. Histamine concentrations in the corpus (no ulcer, median: 151 nmol/g; DU, median: 122 nmol/g) and in the antrum (no ulcer, median: 118 nmol/g; with DU, median: 113 nmol/g) of renal transplant patients, irrespective of ulcer diagnosis, and in patients with a chronic duodenal ulcer (median corpus histamine: 137 nmol/g and median antral histamine: 126 nmol/g) were not different from one another but significantly lower than the corresponding values in normal subjects (median corpus histamine: 241 nmol/g, p less than 0.01, and median antral histamine: 178 nmol/g, p less than 0.05). Histamine concentration in the corpus was significantly higher than in the antrum in all three groups of patients (p less than 0.05). There were no significant differences in histamine methyltransferase activity in any of the groups studied. Mucosal histamine and histamine methyltransferase activity were significantly correlated in the corpus (p less than 0.05) and antrum (p less than 0.02). Plasma concentration of histamine after transplant was higher in the patients who subsequently were discovered to have a duodenal ulcer (p less than 0.05). The occurrence of ulcer after transplantation was not related to the serum creatinine level. The uniform depletion of gastric histamine and increase in circulatory histamine after renal transplantation may be a factor in the pathogenesis of duodenal ulcer disease in this clinical situation.

Campylobacter pylori as a pathogenetic factor in duodenal ulcer: the case for.

This debate addresses whether Campylobacter pylori contributes to the development and maintenance of chronic peptic ulcer disease. C. pylori may be both an aggressive factor and may also impair mucosal defence. C. pylori causes the inevitably ulcer-associated gastritis and duodenitis and eradication of the C. pylori infection is associated with resolution of the inflammation and virtual elimination of the problem of duodenal ulcer relapse. A model is suggested that requires two separate factors to combine to cause chronic duodenal ulcer disease with other environmental factors (e.g. smoking) modifying the interaction between C. pylori and genetic susceptibility. Both genetic susceptibility and C. pylori infection are required to produce duodenal ulcer disease; neither alone is sufficient. C. pylori is the most important factor in the pathogenesis of duodenal ulcer disease because it is the only pathogenetic factor that can be easily reversed by medical therapy.

Antral release of gastrin and somatostatin in duodenal ulcer and control subjects.

Organ culture was used to compare gastrin and somatostatin release from cultured antral mucosa obtained from duodenal ulcer and non-ulcer (control) subjects. In response to dibutyryl cyclic AMP (DBCAMP) cultured antral mucosal explants from patients with a history of duodenal ulcer released a greater proportion of antral gastrin into the medium than did antral mucosal explants from non-ulcer subjects. Somatostatin release from antral mucosa from duodenal ulcer patients was substantially less than somatostatin released by antral explants from non-ulcer subjects. In the non-ulcer subjects there was a direct positive correlation between the amounts of antral somatostatin and gastrin released into the culture medium (r = 0.64, less than p 0.01). In the duodenal ulcer patients, however, there was no correlation between gastrin release and somatostatin release from antral mucosa ( r = 0.09; p greater than 0.2). Results of these studies identify enhanced gastrin release in response to stimulation and decreased release of somatostatin from antral mucosa of duodenal ulcer patients. These alterations in paracrine relationships of antral somatostatin and gastrin in duodenal ulcer subjects may contribute, at least in part, to the pathogenesis of duodenal ulcer disease.

Role of circulating somatostatin in regulation of gastric acid secretion, gastrin release, and islet cell function. Studies in healthy subjects and duodenal ulcer patients.

Studies were designed (a) to determine whether somatostatin is released into the circulation after meals in sufficient amounts to regulate gastric or pancreatic islet function in humans and (b) to investigate the possible role of somatostatin in the pathogenesis of duodenal ulcer disease. Mean plasma somatostatin-like immunoreactivity (SLI) increased from 6.2 +/- 1.5 pg/ml to a peak level of 13.8 +/- 1.3 pg/ml in eight healthy subjects after a 1,440-cal steak meal (P less than 0.005). When somatostatin-14 was infused intravenously, basal and food-stimulated gastric acid secretion and also basal and food-simulated plasma insulin and glucagon concentrations were reduced significantly at mean plasma SLI concentrations within the range seen after a meal. Thus, the amount of somatostatin reaching the systemic circulation after a steak meal was sufficient to inhibit gastric acid secretion and islet cell function. On the other hand, basal and food-stimulated plasma gastrin concentrations were reduced by intravenous somatostatin only at plasma SLI concentrations that were several-fold greater than post-prandial SLI concentrations. Although duodenal ulcer patients had significantly higher basal, food-stimulated, and peak pentagastrin-stimulated gastric acid secretion rates than healthy controls, duodenal ulcer patients and controls had nearly identical basal and food-stimulated SLI concentrations. Moreover, food-stimulated gastric acid secretion and gastrin release were inhibited by intravenous somatostatin to the same extent in ulcer patients and controls. These studies suggest that duodenal ulcer patients release normal amounts of somatostatin into the circulation and that target cells controlling acid secretion and gastrin release are normally sensitive to somatostatin in these patients.

Effects of food on plasma catecholamine and gastrin levels in patients with duodenal ulcer and normal volunteers.

Changes in plasma concentrations of adrenaline, noradrenaline, dopamine and gastrin in response to a standard meal were studied in 6 normal volunteers and 8 patients with chronic duodenal ulcer (DU) disease. Before the meal plasma gastrin and noradrenaline, but not adrenaline or dopamine, were higher in DU patients than in the controls. Food induced significant increments in plasma gastrin and noradrenaline concentration in both groups, whereas plasma adrenaline and dopamine levels remained unchanged. Plasma gastrin and noradrenaline concentrations were higher in DU patients than in the normal controls both during and after the meal. The results do not support the hypothesis that adrenaline is involved in the pathogenesis of duodenal ulcer disease, whereas the role of the increased plasma noradrenaline concentrations in this disease remains unclear.

Antral gastrin and somatostatin concentrations in peptic ulcer patients

As an attempt to approach the pathogenesis of peptic ulcer disease, antral gastrin and somatostatin concentrations were studied in normal subjects, patients with duodenal ulcer and gastric ulcer. In the patients with peptic ulcer, antral somatostatin concentrations were significantly lower than those in normal subjects. In non-ulcer subjects, including normal subjects and patients with atrophic gastritis, antral somatostatin concentrations were correlated inversely with the degree of antral gastritis, while in the patients with peptic ulcer, especially in duodenal ulcer, they were low, irrespective of histological picture of antral mucosa. In the patients with duodenal ulcer, low antral somatostatin concentrations with high antral gastrin/somatostatin ratio may cause increased serum gastrin levels and increased gastric acid secretion. From the above findings, it has been concluded that low antral somatostatin levels may be related to the pathogenesis of duodenal ulcer disease.

Endocrinology of duodenal ulcer.

Several gastrointestinal peptides with proven or suggested endocrine or paracrine functions influence gastric acid secretion, gastrointestinal motility, and mucosal blood flow. Increased or decreased release of such factors could participate in the pathogenesis of duodenal ulcer disease by inducing increased gastric acid concentration in the duodenal bulb. To date, increased stimulation of parietal cells by gastrin has been demonstrated only in patients with gastrinoma, G-cell hyperplasia, gastric outlet obstruction, hyperparathyroidism, excluded antrum, and short bowel syndrome, but not in the usual duodenal ulcer disease. Also, a defective inhibition of parietal cell function by endocrine or paracrine factors, such as gastric inhibitory polypeptide, secretin, somatostatin and vasoactive intestinal polypeptide, seems not to exist in patients with duodenal ulcer disease. However, as long as the physiology of gastrointestinal peptides in gastric secretion and motility is not understood, a possible role of these factors in the pathogenesis of simple duodenal ulcer disease cannot be excluded.