Ian D. Penman

Helicobacter pylori Infection and Abnormalities of Acid Secretion in Patients With Duodenal Ulcer Disease

BACKGROUND & AIMS The mechanism by which Helicobacter pylori predisposes to duodenal ulcers (DUs) remains unclear. The aim of this study was to investigate the effect of the infection on acid secretion. METHODS Acid output was examined basally and in response to gastrin-releasing peptide (GRP) and gastrin in healthy volunteers with and without H. pylori infection and in patients with DUs before and after eradication of the infection. RESULTS Compared with H. pylori-negative healthy volunteers, patients with DUs with H. pylori had the following abnormalities of acid secretion: (1) threefold increase in basal acid output, (2) sixfold increase in acid response to GRP, (3) increased maximal acid response to exogenous gastrin, (4) increased ratio of basal acid output to maximal gastrin-stimulated output, and (5) increased ratio of maximal GRP-stimulated acid output to maximal gastrin-stimulated output. All of these abnormalities resolved fully after H. pylori eradication except for increased maximal acid output to gastrin, which was unchanged. Infected healthy volunteers showed a threefold increase in acid response to GRP that resolved after eradication of H. pylori infection. CONCLUSIONS These disturbances in acid secretion caused by H. pylori infection are consistent with impaired inhibitory control and are likely to be relevant to the mechanism by which the infection predisposes to DU.

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Eradicating Helicobacter pylori infection lowers gastrin mediated acid secretion by two thirds in patients with duodenal ulcer.

Helicobacter pylori (H pylori) raises serum gastrin but it is unclear whether this stimulates increased acid secretion. Gastrin mediated acid secretion and plasma gastrin after the intravenous infusion of gastrin releasing peptide was studied in nine H pylori negative and nine H pylori positive healthy volunteers, and in 11 duodenal ulcer patients. Nine of the last group were re-examined one month after eradication of H pylori. The median acid output (mmol/h) to gastrin releasing peptide (40 pmol/kg/h) in the H pylori positive healthy volunteers was 15.1 (range 3.3-38.3), which was three times that of the H pylori negative healthy volunteers (median = 5.5, range 1.0-9.0) (p < 0.02). The median acid output in the duodenal ulcer patients with H pylori was 37 (range 8.5-57), which was > six times that of the H pylori negative healthy volunteers. Eradication of H pylori in the duodenal ulcer patients lowered their acid secretion by a median of 66% (range 30%-80%) (p < 0.01) and to values equivalent to the H pylori positive healthy volunteers. The pepsin output in response to gastrin releasing peptide followed the same pattern as the acid output. The median plasma gastrin concentrations during gastrin releasing peptide were similar in the H pylori positive duodenal ulcer patients (150 ng/l, range 95-400) and H pylori positive healthy volunteers (129 ng/l, range 23-420) and both were appreciably higher than H pylori negative healthy volunteers (60 ng/l, range 28-135) (p < 0.005 for each). Eradication of H pylori lowered the plasma gastrin in the duodenal ulcer patients to values equivalent to the H pylori negative healthy volunteers. These findings show a threefold increase in acid secretion in H pylori positive healthy volunteers that is explained by H pylori induced hypergastrinaemia and a sixfold increase in acid secretion in the duodenal ulcer patients that is explained by the combination of H pylori induced hypergastrinaemia and an exaggerated acid response to stimulation by gastrin. Eradicating H pylori lowers gastrin mediated acid secretion by 66% in duodenal ulcer patients as a result of the resolution of the hypergastrinaemia. Increased gastrin mediated acid secretion seems to be the key factor in the pathophysiology of duodenal ulceration and explains the role of H pylori infection in the disorder.

A study of the pathogenesis of Helicobacter pylori negative chronic duodenal ulceration.

In the past five years 12 patients have been identified presenting with chronic duodenal ulcer (DU) disease and with no evidence of current or recent Helicobacter pylori (H pylori) infection. Four of them were taking regular non-steroidal anti inflammatory agents, one was subsequently found to have Crohns disease of the duodenum, and one to have the Zollinger-Ellison syndrome. The remaining six patients with idiopathic DU disease were remarkable for their absence of the A1 blood antigen gene. Detailed studies of gastric function were performed in these six patients and compared with H pylori positive patients with DU and with healthy volunteers. The median integrated gastrin response in the patients with idiopathic DU (2810 (range 750-8750) ng/l min) was similar to that of the H pylori positive patients with DU (3355 (550-8725)) and higher than that of the H pylori negative healthy volunteers (560 (225-1125)). The median peak acid output in the patients with idiopathic DU (37 mmol/h, range 17-52) was similar to that of the H pylori positive patients with DU (40 (15-57)) and higher than that of the non-ulcer controls (22 (16-29)). The median percentage of a liquid meal retained in the stomach at 60 minutes was less in the patients with idiopathic DU (23 (15-33)) than in H pylori negative healthy volunteers (34 (30-53) p < 0.01). The median percentage of a solid meal retained at 60 minutes was less in the patients with idiopathic DU (54 (9-83)) than in either H pylori negative healthy volunteers (87 (49-95) p<0.01) or H pylori positive patients with DU (79 (51-100) p<0.01). In conclusion, three abnormalities of gastric function are prevalent in patients with H pylori negative idiopathic DU disease - hypergastrinaemia, increased acid secretion, and the one feature distinguishing them from H pylori positive patients with DU - rapid gastric emptying of both liquids and solids. Each of these abnormalities will increase the exposure of the duodenal mucosa to acid and thus explain its ulceration. The absence of the blood group A1 antigen gene is consistent with a genetic basis for the disturbed gastric function linked to the ABO blood group antigen genes.

A substantial proportion of non-ulcer dyspepsia patients have the same abnormality of acid secretion as duodenal ulcer patients.

Acid secretion in response to gastrin releasing peptide (GRP) is increased six-fold in Helicobacter pylori positive duodenal ulcer (DU) patients and threefold in H pylori positive healthy volunteers, and this fully resolves after eradication of the infection. This study was undertaken to determine whether a proportion of H pylori positive patients with non-ulcer dyspepsia (NUD) have an acid secretion disturbance similar to DU patients. Basal and GRP stimulated gastrin concentrations and acid output were examined in 25 H pylori positive NUD patients and the results compared with those of 25 H pylori positive healthy volunteers, 25 H pylori negative healthy volunteers, and 25 H pylori positive DU patients. Compared with the H pylori negative healthy volunteers, GRP stimulated gastrin was increased approximately three fold in each of the three infected groups. GRP stimulated acid secretion (median, range) was higher in the H pylori positive NUD patients (29.6 mmol/h (5.2-46.5)) (p < 0.005) than in the H pylori positive healthy volunteers (19.0 (1.0-38.3)) (p < 0.001) or H pylori negative healthy volunteers (6.3 (2.8-20.9)) (p < 0.0001). The H pylori positive NUD patients, however, had lower acid output than the DU patients (39.1 (17.9-64)) (p < 0.005). These findings are consistent with approximately 50% of the NUD patients having a similar disturbance of GRP stimulated acid secretion to DU patients.

Low prevalence of Helicobacter pylori in inflammatory bowel disease: association with sulphasalazine.

The prevalence of IgG antibodies to Helicobacter pylori was examined in 110 patients with inflammatory bowel disease (IBD) (63 ulcerative colitis, 47 Crohns disease) and compared with 100 age and sex matched control patients. The overall prevalence of H pylori seropositivity in the IBD patients was 22%, which was significantly less than that of 52% in the controls (p < 0.002). There was no difference in prevalence between ulcerative colitis and Crohns patients. The low seropositivity in the IBD patients resulted from a very low prevalence of 10% in those currently receiving sulphasalazine (n = 40) and similarly low prevalence of 7% in those previously receiving sulphasalazine (n = 30). In those receiving olsalazine or mesalazine and who had never had sulphasalazine, the prevalence of seropositivity was 45%. Further studies using 14C urea breath test and microscopy of antral biopsy specimens confirmed that the negative serology in patients receiving sulphasalazine resulted from absence of the infection rather than absence of humoral immune response to it. In six control patients with H pylori infection, a two week course of sulphasalazine (500 mg four times daily) only caused slight suppression of the 14C urea breath test. In vitro studies failed to show any direct antibacterial effect of sulphasalazine on H pylori. These findings indicate that longterm treatment with sulphasalazine leads to eradication of H pylori infection and that this does not result from a direct antibacterial effect. It may be caused by the drug treating the gastritis and thereby depriving the bacterium of essential nutrients exuded by the inflamed mucosa.

Plasma gastrin concentrations are normal in patients with colorectal neoplasia and unaltered following tumor resection

BACKGROUND/AIMS Previous studies have found that colorectal cancer patients have hypergastrinemia, but most have been inadequately controlled. Preoperative fasting and meal-stimulated gastrin levels were measured in patients with colorectal tumors (n = 42) and in carefully matched controls (n = 34). Helicobacter pylori status was assessed because it causes significant hypergastrinemia. METHODS Plasma gastrin levels were measured by radioimmunoassay. Helicobacter status was assessed using the [14C]urea breath test and serology (immunoglobulin G). RESULTS Preoperatively, fasting plasma gastrin levels were similar in patients with tumors (median, 55 ng/L; interquartile range, 45-82.5) and controls (77.5 ng/L; 53.7-137.5; P = 0.10). Similarly, peak gastrin levels were not significantly different in tumor patients (200 ng/L; 137.5-312.5) and controls (247.5 ng/L; 147.5-375; P = 0.21). The prevalence of H. pylori infection in patients with tumors (60%) and controls (53%) was similar in both groups. Five (20%) tumor patients who were H. pylori-positive preoperatively were negative postoperatively, and their median peak plasma gastrin level decreased from 200 ng/L to 140 ng/L. After these patients were excluded, fasting and peak plasma gastrin concentrations were similar preoperatively and postoperatively. CONCLUSIONS When confounding factors are controlled for, plasma gastrin levels are not increased in colorectal cancer and do not decrease after curative resection. Previously noted decreases in gastrin levels after tumor resection may be attributable to loss of H. pylori infection in some patients, as noted here.

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry

Background Barretts oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. Methods We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008–2010 and 2011–2013). Durability of successful treatment and progression to OAC were also evaluated. Results 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). Conclusions Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2–4% at 1 year in these high-risk patients. Trial registration number ISRCTN93069556.

Omeprazole inhibits colorectal carcinogenesis induced by azoxymethane in rats.

Numerous clinical and experimental studies suggest that gastrin plays an important part in the development of colorectal cancer in humans. This study was done to assess the influence of omeprazole induced hypergastrinaemia on the development of colorectal tumours in an experimental animal model. Forty female Sprague-Dawley rats received either omeprazole (40 mumol/kg) or vehicle (0.25% methylcellulose) by once daily oral gavage throughout the experiment. All animals received 12 consecutive weekly subcutaneous injections of azoxymethane (10 mg/kg/week) beginning at week 6. Serum gastrin concentrations were measured during weeks 1 and 5 and at death (week 27). Chronic omeprazole treatment resulted in appreciable hypergastrinaemia during the study, mean gastrin concentrations in omeprazole treated rats being raised by up to nine to 10 fold, compared with vehicle treated control rats (p < 0.001). Despite this, tumour incidence in the omeprazole group was significantly lower at 63%, compared with 95% in the vehicle only group (p < 0.02). The median number of tumours in the omeprazole group (1) compared with the vehicle group (3) was also significantly lower (p = 0.02). Average tumour size, site distribution, and the comparative frequencies of adenomas and adenocarcinomas were similar in the two groups. This study shows that omeprazole protects against colorectal carcinogenesis in this model despite causing appreciable hypergastrinaemia. The mechanism by which this occurs is unclear and merits further investigation. Because of the compounding protective effects of omeprazole, this model is not a suitable one for studying the longterm trophic effects of gastrin on the colon.

Radiofrequency ablation for early oesophageal squamous neoplasia: Outcomes form United Kingdom registry

AIM To report outcomes on patients undergoing radiofrequency ablation (RFA) for early oesophageal squamous neoplasia from a National Registry. METHODS A Prospective cohort study from 8 tertiary referral centres in the United Kingdom. Patients with squamous high grade dysplasia (HGD) and early squamous cell carcinoma (ESCC) confined to the mucosa were treated. Visible lesions were removed by endoscopic mucosal resection (EMR) before RFA. Following initial RFA treatment, patients were followed up 3 monthly. Residual flat dysplasia was treated with RFA until complete reversal dysplasia (CR-D) was achieved or progression to invasive Squamous cell cancer defined as infiltration into the submucosa layer or beyond. The main outcome measures were CR-D at 12 mo from start of treatment, long term durability, progression to cancer and adverse events. RESULTS Twenty patients with squamous HGD/ESCC completed treatment protocol. Five patients (25%) had EMR before starting RFA treatment. CR-D was 50% at 12 mo with a median of 1 RFA treatment, mean 1.5 (range 1-3). Two further patients achieved CR-D with repeat RFA after this time. Eighty per cent with CR-D remain dysplasia free at latest biopsy, with median follow up 24 mo (IQR 17-54). Six of 20 patients (30%) progressed to invasive cancer at 1 year. Four patients (20%) required endoscopic dilatations for symptomatic structuring after treatment. Two of these patients have required serial dilatations thereafter for symptomatic dysphagia with a median of 4 dilatations per patient. The other 2 patients required only a single dilatation to achieve an adequate symptomatic response. One patient developed cancer during follow up after end of treatment protocol. CONCLUSION The role of RFA in these patients remains unclear. In our series 50% patients responded at 12 mo. These figures are lower than limited published data.