Gastric and duodenal mucosal protein fractional synthesis and growth factor expression in patients with H. pylori-associated gastritis before and after eradication of the organism.

Our purpose was to study the effect of Helicobacter pylori (HP) on mucosal protein fractional synthesis (MPFS) and growth factor expression. 14C-leucine incorporation, and TGF-alpha, beta-FGF, and EGF-receptor levels were assessed in gastric and duodenal mucosa in 20 patients with HP-associated gastritis and repeated after treatment of the gastritis, with or without eradication of the organism. At entry, MPFS in the fundus, antrum, and duodenum was 43.1, 38.2, and 28.3%/day, respectively. Following HP eradication, fundal and antral rates fell to 28.1 and 21.4%/day (P < 0.05), whereas the duodenum was unchanged. MPFS in the patient subset not eradicated remained similar to entry values (35.9, 31.6, and 25.4%/day). Expression of TGF-alpha, beta-FGF, and EGF receptors was unchanged. Eradication of HP results in reduction of gastric, but not duodenal, MPFS and has no effect on the growth factors measured. Increased MPFS associated with HP gastritis may relate to the potential for neoplastic transformation.

Peptic ulcer disease.

PURPOSE OF REVIEW: This review reports and attempts to place in some context current key observations in the literature, as they relate to peptic ulcer disease. RECENT FINDINGS: Focus areas in this review are general, the usefulness of symptom-based triage in management decision making and critical review of current practice as it relates to foregut malignancy; Helicobacter pylori, important observations regarding gastric cancer prevention are presented, the role of the organism in "acid rebound" is discussed, and further evidence to support the role of H. pylori eradication in peptic ulcer disease is provided; medication, a number of studies comparing steady state and onset of action efficacy of current proton pump inhibitors at a gastric pH level are reviewed and a new agent is introduced. Problems with and strategies for the safe use of antithrombotic agents are reviewed, and exciting data with regard to a new class of nonsteroidal antiinflammatory drug are provided, now at the "proof of concept" stage. SUMMARY: The review period's main "new" information relates to the nonsteroidal antiinflammatory drugs in which a number of exciting agents are being developed. Although inconclusive, the observations with regard to the effect of H. pylori eradication on gastric carcinogenesis is likely to lead to more work in this field.

The management of peptic ulcer disease.

PURPOSE OF REVIEW: The period under review has seen little evolution in our understanding of the empiric management of dyspepsia. The role of Helicobacter pylori in this setting remains controversial, and a policy of risk stratification with the prudent use of test and treat and symptomatic therapy, with endoscopy for nonresponsive cases, seems to have some support from the literature in this period. RECENT FINDINGS: The management of nonsteroidal antiinflammatory drug-associated and aspirin-associated complications has received a lot of attention in the period under review. The COX-2 selective agents have maintained their reputation as safer (but not "safe") options, although some of the original work with one of these agents has been rigorously interrogated and found wanting. Studies in the review period have focused our attention on the less than satisfactory protection of proton pump inhibitor cotherapy, the site-specific nature of ulcer recurrences (which may have therapeutic implications), lower gastroenterology complications associated with NSAID use, and the beneficial effect of proton pump inhibitor cotherapy for patients receiving low-dose aspirin. One should also expect a lot more information in the future with regard to the use of the nitric oxide donating class of nonsteroidal antiinflammatory drugs and aspirin. SUMMARY: Findings are presented that suggest that the H.pylori stool antigen test is not as reliable as the urea breath test, while the most promising "new therapy" for H. pylori is not new, but rather an amalgam of some older drugs combined in a new "quadruple" therapy strategy, which shows some promise.

The pepsinogen releasing effect of Helicobacter pylori lipopolysaccharide.

BACKGROUND: Helicobacter pylori lipopolysaccharide (LPS) affects pepsinogen release by a nontoxic mechanism. We hypothesized that this effect was characteristic of the organism and related to the clinical status of the strain. MATERIALS AND METHODS: LPS was isolated from 11 H. pylori strains whose pathogenic profile was known and four other nongastric bacteria. The effects of luminal LPS on guinea pig gastric mucosal pepsinogen release was evaluated using the Ussing chamber technique. CCK-8 (10(-9)M) was used as a positive control. RESULTS: H. pylori LPS dose-dependently stimulated pepsinogen release with a maximal stimulation at 250 microg/ml (approximately 4500; p < .001 vs. control). LPS from other Helicobacter or Campylobacter species had no effect on pepsinogen release. ANOVA demonstrated significant differences in the efficacies of pepsinogen release between the 11 clinical H. pylori strains (p < .0001) despite the fact that they were all cagA+ and 90 had the cytotoxic vacA subtype s1. Physical and chemical disruption of the LPS suggested that both the structure and the carbohydrate composition of this molecule may play a critical role in pepsinogen release. Polymyxin B partly (p < .03) inhibited and dephosphorylation completely inhibited (p = .0002) LPS-stimulated pepsinogen release. CONCLUSION: Pepsinogen release is an innate property of all cagA+H. pylori LPS. The structure of the molecule and composition of side-chains are important in this response which appears to be partially lipid A driven.

Peptic ulcer disease.

The introduction of the "Maastricht 2-2000" document provides some guidance with regard to the management of Helicobacter pylori infection in both primary and specialist practice settings, albeit primarily in the European setting. The putative role of H. pylori in gastric carcinogenesis was supported by a further study. Studies on the natural history of peptic ulcer disease (PUD) highlight the particular vulnerability of the elderly patient to PUD and its complications, and focus attention on targeted intervention in this group, particularly the avoidance of nonsteroidal antiinflammatory drugs (NSAID). Little has evolved with regard to the introduction of new NSAID, but reports indicate the potential association of cyclooxygenase-2 (COX 2)-selective agent use with an increased risk of cardiovascular events. The role of H. pylori and NSAID as risk factors for peptic ulcer disease and its complications is again explored, and both meta-analysis and clinical studies provide some evidence of their synergistic effect. The introduction of esomeprazole, the S-isomer of omeprazole, has widened the clinician's therapeutic choice; the true value of this agent remains to be determined.

The medical treatment of peptic ulcer disease.

There is continued interest in the role of H. pylori in both uninvestigated and non ulcer dyspepsia. The literature on this issue provided interesting, if at times conflicting findings, leaving the clinician with little choice but to use clinical judgment when dealing with these patients. On the Therapeutic front, a "new" proton pump inhibitor, with impressive early efficacy data has been launched, while an i.v. proton pump inhibitor formulation has reached a number of markets. Emerging data on the use of potent acid suppression in especially GI bleeding will almost certainly impact on the use of these agents. The gastrointestinal effects of low dose aspirin use have received attention, while the COX1-sparing agents have now started to impact on clinical practice. Two large clinical outcomes studies with these agents have been published. Both indicate at least some benefit, but raise interesting questions with regard to the use of these agents in the clinical setting.

The treatment of peptic ulcer disease.

There is a continuation of the debate on the management of dyspepsia while the role of Helicobacter pylori in duodenal ulcer disease is being questioned with renewed vigor, specifically in the United States. The interaction of NSAIDs and H. pylori provided some interesting, if at times confusing, literature while the debate on the safety of long-term acid suppression remained unresolved. There were some interesting developments with regard to therapeutic agents during this period. A fourth proton pump inhibitor was introduced to the market while cisapride, a drug previously considered safe, was effectively withdrawn from the North American market because of safety concerns. More data on the COX-1-sparing agents became available, and their impressive gastrointestinal safety profile was confirmed. It was noted, however, that the incidence of dyspepsia, experienced by users of these drugs, may remain a problem.

Helicobacter pylori in Africa: observations on an 'enigma within an enigma'.

BACKGROUND: We conducted a retrospective literature review of all the data published on Helicobacter pylori in Africa in order to test whether the prevalence of diseases associated with this organism differs from that in developed nations. METHODS: Both sero-epidemiological (n = 8) as well as prospective endoscopic studies in subjects with either dyspepsia or epigastric pain (n = 23) and one retrospective study were available for analysis. RESULTS: Sero-epidemiology confirmed both the early age of acquisition in children (50% by 10 years) as well as the high prevalence of the organism (61%) in adult asymptomatic individuals. Endoscopic studies in dyspeptic individuals revealed the presence of the organism in 72%. Duodenal ulceration was noted in 26% of 3473 cases and in these, H. pylori was present in 90%. An association of gastric metaplasia with duodenal ulceration was identified in the one study in which it was investigated. Gastric ulceration occurred approximately four-fold less frequently (7% of 2286 cases) than duodenal ulceration and the organism was evident in 75% of the gastric ulceration cases. Findings of intestinal metaplasia (14%) and gastric cancer (3.4%) were not infrequent, but the paucity of accurate epidemiological data made it difficult to establish a correlation between the two. CONCLUSION: It would appear that prospective endoscopic-based studies in African subjects may question the standard dogma of a low prevalence of H. pylori-associated diseases in Africa. Further research is clearly required.

The treatment of peptic ulcer disease.

The literature published in the period under review identified some areas of key clinical and scientific importance in the treatment of peptic ulcer disease. Attention was drawn to the possibility that Helicobacter pylori may be less important as an etiologic factor in ulcer disease in the United States than in the rest of the world. The usual large number of papers addressed various treatment regimens, and the issue of H. pylori resistance to antibiotics was prominent. The introduction of the cyclooxygenase enzyme 2 (COX-2)-specific inhibitors promises to significantly affect nonsteroidal anti-inflammatory drug (NSAID) gastropathy. The review period produced some excellent papers (mainly review papers) on this topic, but there is a paucity of peer-reviewed data on the clinical application of COX-2 NSAIDs. Perhaps more important is that some authors, using a variety of animal models, protested the blithe acceptance of the COX-2 concept, questioning the idea of "specificity" and identifying possible problems with respect to ulcer healing. Observations of potential clinical importance with regard to the phenomenon of acid rebound after proton-pump inhibitor therapy were presented, and the role of H. pylori in the management of nonulcer dyspepsia remains controversial, despite the publication of three of the best-designed studies to date on this important topic.

Helicobacter pylori eradication and ulcer healing with daily lansoprazole, plus 1 or 2 weeks co-therapy with amoxycillin and clarithromycin.

BACKGROUND: Proton pump inhibitor based combination therapy is one standard strategy for Helicobacter pylori eradication. AIM: To compare the eradication and duodenal ulcer healing efficacy of two 2-week, single dose, lansoprazole based combination therapies. METHODS: Healthy adult patients with endoscopically confirmed, H. pylori associated duodenal ulcer disease (3 mm > ulcer < 20 mm) were eligible for the study. All patients received a 14 day course of lansoprazole 30 mg o.m., and were randomized to receive either 7 or 14 days of amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. Patients were endoscoped at entry and 14-17 days later. Symptomatic, unhealed patients received a further 14 days of therapy with lansoprazole 30 mg o.m. Eradication was confirmed a minimum of 28 days after cessation of all therapy by urease reaction and histological assessment of gastric body and antral biopsies (three biopsies each site). RESULTS: Sixty-two patients were randomized to a treatment arm, of which 58 could be included in an intention-to-treat and key-point-available analysis. H. pylori eradication rates were identical, at 93% (95% CI: 73-98% (1 week), 78-99% (2 week)). In the combined group, all but 13 ulcers were healed at 2 weeks; six required further therapy because of symptoms, while six of the seven asymptomatic patients went on to heal. CONCLUSION: An eradication regimen, based on a 2-week course of single dose lansoprazole with 1 week of antibiotic co-therapy, is effective in eradicating H. pylori, while the 2 weeks of acid suppression is usually effective in duodenal ulcer healing.

Basal and pentagastrin stimulated acid secretion in duodenal ulcer subjects before and after Helicobacter pylori eradication: a 12-month follow-up study.

BACKGROUND: The effect of infection by Helicobacter pylori on gastric physiology in duodenal ulcer subjects is controversial. There is evidence that the infection is associated with abnormalities in gastrin homeostasis. Consistent changes in pentagastrin-stimulated acid secretory status have proved difficult to establish. This may be because patients have been studied too soon after Helicobacter pylori eradication. AIMS: To study the immediate and longer term effect of Helicobacter pylori eradication on basal and pentagastrin-stimulated acid secretion in duodenal ulcer subjects. PATIENTS AND METHODS: Patients with active duodenal ulcer disease were studied. Ulcers were healed with sucralfate 2 g bd or ranitidine 300 mg nocte. Helicobacter pylori eradication was attempted with bismuth-based "Triple Therapy", and the nine patients in whom the organism was successfully eradicated were followed and studied over the 12-month period. Acid secretion was studied at entry (prior to the initiation of therapy), following healing, following eradication and 12 months later. Basal, low dose (0.1 microgram/kg) and high dose (6 micrograms/kg) pentagastrin-stimulated acid secretion was determined. RESULTS: Whilst there was a tendency for basal and low dose-stimulated acid secretion to fall following eradication, in this study only the reduction in high dose-stimulated acid secretion achieved significance following eradication (entry mean = 59.6, post eradication mean = 49.6, p < 0.03). This effect of eradication on high dose pentagastrin-stimulated acid secretion was also seen at the 12-month study (mean = 48.9, p < 0.02 versus entry). CONCLUSION: The findings of this study suggests that maximally stimulated acid secretion is modestly, albeit significantly, reduced following Helicobacter pylori eradication and that this effect persists.

Two-week course of pantoprazole combined with 1 week of amoxycillin and clarithromycin is effective in Helicobacter pylori eradication and duodenal ulcer healing.

BACKGROUND: Experience with proton pump inhibitor-based triple therapy is predominantly with omeprazole-containing regimens. AIM: To investigate the efficacy of a pantoprazole-based regimen, with either a 1 or 2-week course of antibiotic co-therapy, in eradicating H. pylori, healing duodenal ulcers and to assess the antibiotic sensitivity profiles of isolated H. pylori strains. METHODS: A single-blind, multicentre, parallel group comparison of patients with endoscopically proven, H. pylori associated, active duodenal ulceration. All patients received pantoprazole, 40 mg b.d. for 2 weeks. Patients were randomized to receive either 1 or 2 weeks of therapy with amoxycillin, 1 g b.d. and clarithromycin 500 mg b.d. Patients were endoscoped at entry, at 14 days and a minimum of 4 weeks after cessation of all therapy. H. pylori status was determined by urease reaction, histological assessment and culture from antral and body biopsies. Antibiotic sensitivity was determined using the agar dilution technique. RESULTS: Sixty-seven patients were randomized. One week co-therapy (n=33): eradication efficacy, ITT= 79% (95% CI: 61-91%); ulcer healing efficacy (at 6-week visit)=88% (95% CI: 72-97%). Two-week co-therapy (n=34): eradication efficacy, ITT=91% (95% CI: 76-98%: ulcer healing efficacy= 88% (95% CI: 73-97%). Both regimens were well tolerated and no primary antibiotic resistance was noted. CONCLUSION: Pantoprazole-based triple therapy, with either 1 or 2 weeks of co-therapy with amoxycillin and clarithromycin, is effective in eradicating H. pylori and healing duodenal ulceration.

Changes in mucosal levels of transforming growth factor-alpha from the oxyntic region and ulcer site during duodenal ulcer healing with ranitidine or sucralfate.

Changes in the levels of transforming growth factor-alpha (TGF-alpha) in gastric mucosa during ulcer healing were studied in 24 patients with endoscopically confirmed duodenal ulcers, treated either with ranitidine (300 mg daily, at night) or with sucralfate (2 g twice daily). Endoscopic biopsies were taken from the gastric fundus and from the ulcer margin at baseline and after 7-10 days of treatment. TGF-alpha levels were determined by radioimmunoassay in paired samples from 22 patients (fundal) and 18 patients (duodenal). There were no significant changes in TGF-alpha levels in the fundus of the whole group or of either treatment group. At the ulcer site, however, there was a significant increase in TGF-alpha levels in the whole group (from 16.4 to 33 pg/mg protein (medians); P < 0.005), and an increasing trend was seen in both treatment groups but was statistically significantly only in the group treated with sucralfate (P < 0.03).

Helicobacter pylori: therapeutic targets.

Helicobacter pylori is now considered a major pathogen of the upper gastrointestinal tract. It is seen as an important cause of peptic ulceration not associated with NSAID use. It is also increasingly linked to other diseases of the GI tract, although the relationship between the organism and conditions such as gastric cancer, non-ulcer dyspepsia and gastroesophageal reflux disease is not as clear as is the case in peptic ulcer disease. This is probably because of a lack of well-performed, statistically powerful, prospective therapeutic trials that indicate that H. pylori eradication is of benefit in these diseases. The high infection rate without overt disease seen in many populations, especially from developing countries, probably contributes to this "credibility gap." While we have excellent therapeutic regimens available at this time, rational targeting requires that the objective evidence in favor of therapeutic intervention in upper GI disease, as well as the local H. pylori epidemiology, needs to be considered.

Effect of chronic duodenal ulceration and its treatment with lanzoprazole or sucralfate on gastroduodenal mucosal protein turnover and TGF-alpha, bFGF, and EGF receptor expression in humans.

In order to investigate whether chronic duodenal ulcer disease is a consequence of disturbed mucosal turnover and growth factor expression, we studied 16 patients with duodenal ulcers before, during, and after endoscopic healing with lansoprazole or sucralfate. Before treatment, gastric fundal and antral mucosal protein turnover rates were higher in patients than controls, without parallel increases in growth factors. Both forms of therapy produced similar changes, with overall increases in duodenal mucosal turnover and transforming growth factor-alpha (TGF-alpha) and epidermal growth factor receptor (EGF-r) levels. Measurements after healing showed persistent elevations of mucosal turnover in the antrum and duodenum and depressions of basic fibroblast growth factor (bFGF) in gastric fundal and duodenal mucosa. We conclude that mucosal turnover is abnormally high in patients with chronic duodenal ulcer disease and is not easily explained by growth factor changes. The failure of lansoprazole and sucralfate to normalize rates, despite endoscopic healing, may explain the high ulcer relapse rates in non-HP-eradicated patients.

Changes in acid secretion over the years. A 30-year longitudinal study.

We studied the effect of aging on gastric acid secretion in 11 physicians who had augmented histamine tests while at medical school in 1962. One of them had a duodenal ulcer at the time. The augmented histamine test was repeated in 1991 and, in addition, upper gastrointestinal endoscopy was done to exclude peptic ulcer and to obtain biopsies for histologic analysis and assessment of Helicobacter pylori status. The mean basal acid output decreased from 7.3 to 1.9 mEq/hr during the 30-year period of follow-up (p < 0.001), and the mean maximum acid output decreased from 29.9 to 20.3 mEq/hr (p < 0.01). The maximum acid output data showed a profound decrease in 4 of the 11 participants, a lesser decrease in 4, and a minimal increase in the remaining 3. Histologic analysis suggested a greater likelihood of atrophic gastritis, H. pylori infection, or both in participants showing a pronounced decrease in acid secretion with aging.

The pivotal role of John S. Edkins in the discovery of gastrin.

John Sydney Edkins was born in London in 1863. After gaining two open scholarships, he attended Caius College, Cambridge and studied physiology under the tutelage of J.N. Langley and M. Foster. During this period he published on the chemical nature of pepsinogen with Langley. After qualifying as a medical doctor, he worked in Manchester before returning to London, where he succeeded E. Klein as Head of Physiology at St. Bartholomew's. For financial reasons he also worked part time at Bedford College for Women. In 1902 Bayliss and Starling overturned Pavlov's doctrine of the nervous regulation of gastrointestinal function by discovering the pancreatic secretagogue secretin-the first identifiable chemical messenger. Edkins applied a similar rationale to the stomach and in a classic series of experiments noted that injection of a pyloric mucous membrane extract resulted in gastric acid and pepsin secretion in anesthetized cats. In 1905 he named this putative active agent "gastrin." Although his ideas were initially accepted, the discovery of histamine in 1910 and the identification that extracts from other tissues had a similar physiologic effect raised serious questions regarding the validity of the existence of gastrin. Somewhat discouraged, Edkins pursued the teaching and training of women physiologists at Bedford College, where he later became Chairman of Physiology. Outside of science he successfully pursued other interests and became President of the British Croquet Association. The demonstration that gastrin was a unique antral stimulant of acid secretion by Komarov in 1938 was followed by the purification and elucidation of its chemical structure by Gregory and Tracy in 1964. Their work allowed final validation of Edkins' original hypothesis. Edkins died in London in 1940, not only fated to predecease the vindication of his hypothesis but unable to witness the evolution of his discovery into a paradigm for the hormonal regulation of secretory and proliferative cellular activity.

Diagnostic pitfalls and therapeutic strategies in the treatment of pancreatic duct haemorrhage.

Haemorrhage via the pancreatic duct, a rare cause of upper gastrointestinal bleeding (GIB), often poses a diagnostic dilemma. We analysed our experience with 10 patients (8 men, 2 women; mean age 44 years, range 34-62) treated during a 12 year period. All had a history of alcohol abuse and presented with major upper GIB requiring a median of 8 units (range 2-40) blood transfusion. Nine had upper abdominal pain at the time of admission and nine had a history of pancreatitis. Upper gastroduodenal endoscopy (median 4; range 1-9), was diagnostic in only one. Side-viewing endoscopy showed bleeding from the pancreatic duct in 7 of 8 patients. Visceral aneurysms were demonstrated in 7 of 9 patients in whom coeliac angiography was carried out: (splenic artery 4, gastroduodenal artery 2, and pancreaticoduodenal artery 1). Two of 4 selective embolisations were successful. Six patients underwent distal pancreatectomy, 1 had gastroduodenal artery ligation and 1 died of coagulopathy following a total pancreatectomy. Pancreatic duct haemorrhage should be considered in patients with unexplained recurrent upper GIB, alcohol abuse and epigastric pain, particularly in those with established chronic pancreatitis. Selective angiography is essential for diagnosis and management. For bleeding sites in the head of the pancreas, embolisation should be attempted to avoid major resection. Distal pancreatectomy is preferred for splenic artery lesions.

A trial of lansoprazole in refractory gastric ulcer.

BACKGROUND: The proton-pump inhibitor, lansoprazole, a more potent gastric acid inhibitor with a longer action than H2-receptor antagonists, should heal refractory gastric ulcers more effectively. METHODS: Lansoprazole's efficacy in healing refractory gastric ulcer(s) (i.e. after 6 weeks of treatment with H2-receptor antagonists, antacids or sucralfate at recommended dosages, and/or a relapse within 1 year of documented gastric ulcer), was compared by a two-dose regimen in a four-centre, randomized, parallel group study. One hundred and eighteen patients (59 per group) with an endoscopically confirmed gastric ulcer > or = 3 mm, received lansoprazole 30 or 60 mg daily. We assessed efficacy endoscopically at 4 and 8 weeks, and again after documented healing during a maintenance phase of lansoprazole 30 mg/day at 2 and 4 months. RESULTS: Demographic and anthropometric data were comparable. Healing rates at 4 weeks were 63% (30 mg) vs. 66% (60 mg) (95% CI, -14 to 21%) and cumulatively at 8 weeks, 83% (30 mg) vs. 81% (60 mg) (95% CI, -12 to 16%). Two and 4 months after documented healing, 86% and 78% of intention-to-treat patients remained in remission. CONCLUSION: Lansoprazole 30 or 60 mg/day appear equally effective in healing refractory gastric ulcers, while maintenance therapy of 30 mg/day effectively prevented an ulcer relapse.