Stuart Ballantyne

Severe reflux disease is associated with an enlarged unbuffered proximal gastric acid pocket

Background: An unbuffered pocket of highly acidic juice is observed at the gastric cardia after a meal in healthy subjects. Aims: To compare the postprandial acid pocket in healthy subjects and patients with severe reflux disease and define its position relative to anatomical and manometric landmarks. Methods: 12 healthy subjects and 16 patients with severe reflux disease were studied. While fasted, a station pull-through was performed using a combined dual pH and manometry catheter. Position was confirmed by radiological visualisation of endoscopically placed radio-opaque clips. The pull-through study was repeated 15 min after a standardised fatty meal. Barium meal examination was performed before and following the meal. Results: A region of unbuffered acid (pH ⩽2) immediately distal to the proximal gastric folds was more frequent in reflux patients (23/32 studies) than in healthy subjects (11/24) (p<0.05). This unbuffered acid pocket was longer in the reflux patients than in the healthy subjects (median length 3 cm (range 1–15) vs 2 cm (range 1–5); p<0.05). The acid pocket extended proximally as far as the proximal gastric folds in the patients but stopped a median of 1.1 cm distal in healthy subjects (p = 0.005). In healthy subjects the acid pocket occupied the distal portion of the sphincter which opened postprandially, whereas in reflux patients it corresponded to the proximal displacement of the gastric folds—that is, hiatus hernia. Conclusion: This enlarged region of unbuffered postprandial acidic juice observed in the patients just below the gastro-oesophageal junction may contribute to the aetiology of severe reflux disease.

Central Obesity in Asymptomatic Volunteers Is Associated With Increased Intrasphincteric Acid Reflux and Lengthening of the Cardiac Mucosa

BACKGROUND & AIMS In the West, a substantial proportion of subjects with adenocarcinoma of the gastric cardia and gastroesophageal junction have no history of reflux. We studied the gastroesophageal junction in asymptomatic volunteers with normal and large waist circumferences (WCs) to determine if central obesity is associated with abnormalities that might predispose individuals to adenocarcinoma. METHODS We performed a study of 24 healthy, Helicobacter pylori-negative volunteers with a small WC and 27 with a large WC. Abdominal fat was quantified by magnetic resonance imaging. Jumbo biopsy specimens were taken across the squamocolumnar junction (SCJ). High-resolution pH-metry (12 sensors) and manometry (36 sensors) were performed in upright and supine subjects before and after a meal; the SCJ was visualized fluoroscopically. RESULTS The cardiac mucosa was significantly longer in the large WC group (2.5 vs 1.75 mm; P = .008); its length correlated with intra-abdominal (R = 0.35; P = .045) and total abdominal (R = 0.37; P = .034) fat. The SCJ was closer to the upper border of the lower esophageal sphincter (LES) in subjects with a large WC (2.77 vs 3.54 cm; P = .02). There was no evidence of excessive reflux 5 cm above the LES in either group. Gastric acidity extended more proximally within the LES in the large WC group, compared with the upper border (2.65 vs 4.1 cm; P = .027) and peak LES pressure (0.1 cm proximal vs 2.1 cm distal; P = .007). The large WC group had shortening of the LES, attributable to loss of the distal component (total LES length, 3 vs 4.5 cm; P = .043). CONCLUSIONS Central obesity is associated with intrasphincteric extension of gastric acid and cardiac mucosal lengthening. The latter might arise through metaplasia of the most distal esophageal squamous epithelium and this process might predispose individuals to adenocarcinoma.

Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder

Investigation of transitional cell carcinoma of the urinary bladder (TCC) patients classified by recurrence and/or progression has demonstrated that loss of chromosome 9, as detected by FISH analysis of the pericentromeric classical satellite marker at 9q12, occurs early. A total of 105 TCCs from 53 patients were analysed in situ by two independent observers for loss of chromosome 9 using quantitative fluorescence in situ hybridization (FISH). All 53 primary tumours were evaluated for chromosomes 9, 7 and 17. Normal ranges for chromosomal copy number were defined for normal skin epidermis and bladder epithelium. Values for chromosome 9 copy number outwith the range 1.51-2.10 (mean +/- 3 x s.d. of normal values) were significantly abnormal. Twenty-five TCCs were detected with consistent monosomic scores. Of 89 TCCs, in which multiple tumour areas were analysed, 85 tumours (96%) demonstrated the same chromosome 9 copy number in all areas (2-6) analysed; only three tumours demonstrated heterogeneity for this locus. A total of 36% (12 out of 33) of patients with subsequent disease recurrence demonstrated loss of chromosome 9 in their primary and all subsequent TCCs analysed. Only a single patient (n = 20) with non-recurrent TCC showed loss of chromosome 9 (P = 0.0085). Of 53 primary tumours, eight showed significant elevation of chromosome 17. Of these patients, six demonstrated elevation in chromosome 7 copy number. No abnormalities were observed in non-recurrent patients. This study describes rapid quantitation of chromosomal copy number by FISH using a pericentromeric probe for chromosome 9 in TCC of the urinary bladder. Routinely fixed and processed material was evaluated without disaggregation. Strict quality control of FISH demonstrated that this technique was reproducible in a clinical environment and could be used to detect genetic changes relevant to patient outcome. It is proposed that loss of chromosome 9 from primary TCC of the urinary bladder identified patients at high risk of recurrence and possible progression.

Aneusomy of chromosomes 7 and 17 predicts the recurrence of transitional cell carcinoma of the urinary bladder

Objective To determine if changes in chromosome 7 and 17 copy number can be used to predict recurrence in patients with primary noninvasive (pTa) or superficially invasive (pT1) transitional cell carcinoma (TCC) of the urinary bladder.

Ectopic pancreatic-type malignancy presenting in a Meckel's diverticulum: a case report and review of the literature

BackgroundNeoplasms arising from Meckels diverticulae reported in the literature are mainly carcinoid tumours, gastrointestinal stromal tumours, and gastric or intestinal adenocarcinomas.Case presentationWe describe a 50-year-old man who presented with rectal bleeding and anaemia, later found to be caused by a pancreatic adenocarcinoma arising from ectopic pancreatic tissue in a Meckels diverticulum. The tumour was unfortunately highly aggressive, and the patient passed away within 5 months of symptom onset.ConclusionWe believe this is the first case of pancreatic adenocarcinoma in a Meckels diverticulum to be reported in the literature. The diagnosis of Meckels should be considered in patients with acute gastrointestinal complaints; when found incidentally at laparotomy, it should be carefully examined for any gross abnormality and resection should be considered.

In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity

Introduction Recently, we showed that the length of cardiac mucosa in healthy volunteers correlated with age and obesity. We have now examined the immunohistological characteristics of this expanded cardia to determine whether it may be due to columnar metaplasia of the distal oesophagus. Methods We used the squamocolumnar junction (SCJ), antral and body biopsies from the 52 Helicobacter pylori-negative healthy volunteers who had participated in our earlier physiological study and did not have hiatus hernia, transsphincteric acid reflux, Barretts oesophagus or intestinal metaplasia (IM) at cardia. The densities of inflammatory cells and reactive atypia were scored at squamous, cardiac and oxyntocardiac mucosa of SCJ, antrum and body. Slides were stained for caudal type homeobox 2 (CDX-2), villin, trefoil factor family 3 (TFF-3) and liver–intestine (LI)-cadherin, mucin MUC1, Muc-2 and Muc-5ac. In addition, biopsies from 15 Barretts patients with/without IM were stained and scored as comparison. Immunohistological characteristics were correlated with parameters of obesity and high-resolution pH metry recording. Results Cardiac mucosa had a similar intensity of inflammatory infiltrate to non-IM Barretts and greater than any of the other upper GI mucosae. The immunostaining pattern of cardiac mucosa most closely resembled non-IM Barretts showing only slightly weaker CDX-2 immunostaining. In distal oesophageal squamous mucosa, expression of markers of columnar differentiation (TFF-3 and LI-cadherin) was apparent and these correlated with central obesity (correlation coefficient (CC)=0.604, p=0.001 and CC=0.462, p=0.002, respectively). In addition, expression of TFF-3 in distal oesophageal squamous mucosa correlated with proximal extension of gastric acidity within the region of the lower oesophageal sphincter (CC=−0.538, p=0.001). Conclusions These findings are consistent with expansion of cardia in healthy volunteers occurring by squamo columnar metaplasia of distal oesophagus and aggravated by central obesity. This metaplastic origin of expanded cardia may be relevant to the substantial proportion of cardia adenocarcinomas unattributable to H. pylori or transsphincteric acid reflux.

Effect of nitrite delivered in saliva on postprandial gastro-esophageal function

Abstract Objective. Acid reflux produces troublesome symptoms (heartburn) and complications including esophagitis, Barretts esophagus, and adenocarcinoma. Reflux occurs due to excessive and inappropriate relaxation of the lower esophageal sphincter. An important mediator of this is nitric oxide, high concentrations of which are generated within the lumen when swallowed saliva meets gastric acid. Saliva contains nitrite, derived from the enterosalivary recirculation of dietary nitrate, which is reduced to nitric oxide by gastric acid. The aim of this study was to investigate whether salivary nitrite contributes to dysfunction of the lower esophageal sphincter. Materials and methods. In 20 volunteers, studies of gastro-esophageal function were performed on four separate days, following consumption of a standardized meal, with saliva nitrite concentrations modified differently each day by intra-oral nitrite infusion. Results. The infusions produced an appropriate range in saliva nitrite concentrations, from below to well above the physiological range. The standardized meal induced expected physiological changes in gastro-esophageal function confirming the recordings were sensitive and robust. Esophageal acid exposure (primary outcome) was similar on each study day. Secondary outcomes, including number and duration of reflux events, rate of transient lower esophageal sphincter relaxations, lower esophageal sphincter pressure and rate of gastric emptying were also unaffected by variations in saliva nitrite concentration. Conclusions. Nitrite in swallowed saliva does not modify gastro-esophageal junction function or predispose to gastro-esophageal reflux. The wide range in saliva nitrite concentrations, the sensitivity of the physiological recordings and the number of subjects studied make it very unlikely that an effect has been missed.

The gastric acid pocket is attenuated in H. pylori infected subjects

Objective Gastric acid secretory capacity in different anatomical regions, including the postprandial acid pocket, was assessed in Helicobacter pylori positive and negative volunteers in a Western population. Design We studied 31 H. pylori positive and 28 H. pylori negative volunteers, matched for age, gender and body mass index. Jumbo biopsies were taken at 11 predetermined locations from the gastro-oesophageal junction and stomach. Combined high-resolution pH metry (12 sensors) and manometry (36 sensors) was performed for 20 min fasted and 90 min postprandially. The squamocolumnar junction was marked with radio-opaque clips and visualised radiologically. Biopsies were scored for inflammation and density of parietal, chief and G cells immunohistochemically. Results Under fasting conditions, the H. pylori positives had less intragastric acidity compared with negatives at all sensors >1.1 cm distal to the peak lower oesophageal sphincter (LES) pressure (p<0.01). Postprandially, intragastric acidity was less in H. pylori positives at sensors 2.2, 3.3 and 4.4 cm distal to the peak LES pressure (p<0.05), but there were no significant differences in more distal sensors. The postprandial acid pocket was thus attenuated in H. pylori positives. The H. pylori positives had a lower density of parietal and chief cells compared with H. pylori negatives in 10 of the 11 gastric locations (p<0.05). 17/31 of the H. pylori positives were CagA-seropositive and showed a more marked reduction in intragastric acidity and increased mucosal inflammation. Conclusions In population volunteers, H. pylori positives have reduced intragastric acidity which most markedly affects the postprandial acid pocket.

Hiatus hernia in healthy volunteers is associated with intrasphincteric reflux and cardiac mucosal lengthening without traditional reflux

Background and aims Hiatus hernia (HH) is a key mediator of gastro-oesophageal reflux disease but little is known about its significance in the general population. We studied the structure and function of the gastro-oesophageal junction in healthy volunteers with and without HH. Methods We compared 15 volunteers with HH, detected by endoscopy or MRI scan, but without gastro-oesophageal reflux disease with 15 controls matched for age, gender and body weight. Jumbo biopsies were taken across the squamocolumnar junction (SCJ). High-resolution pH metry (12 sensors) and manometry (36 sensors) were performed upright and supine, before and after a meal. The SCJ was marked with an endoscopically placed clip and visualised fluoroscopically. Results Cardiac mucosa was longer in volunteers with HH (3.5 vs 2.5 mm, p=0.01). There was no excessive acid reflux 5 cm above the upper border of the lower oesophageal sphincter (LOS) in either group but those with HH had short segment reflux 11 mm above the pH transition point after the meal when supine (pH<4 for 5.5% vs 0.3% of time, p=0.01). The SCJ and pH transition point were proximally displaced within the gastro-oesophageal junction in those with HH versus controls (p<0.05). The pH transition point was proximal to the peak LOS pressure point in HH subjects but distal to it in controls after the meal (p<0.05). When supine, the postprandial pH transition point crossed the SCJ in those with HH (p=0.03). Conclusions Healthy volunteers with HH have increased intrasphincteric reflux and lengthening of cardiac mucosa in the absence of traditional transsphincteric reflux.

PWE-071 The Majority of H. Pylori Infected Subjects Have Reduced Intragastric Acidity and Parietal Cell Density which is Most Marked Close to The Gastroesophageal Junction: Abstract PWE-071 Table 1

Introduction A negative association exists between H. pylori infection and both gastroesophageal reflux disease and oesophageal adenocarcinoma. The great majority of the H. pylori infected population are asymptomatic, so we studied healthy volunteers to determine if the infection is associated with changes to the acid secretory capacity of gastric mucosa which may protect individuals from acid reflux. Methods We studied 31 H . pylori positive and 29 H . pylori negative volunteers, matched for age and gender. Jumbo biopsies were taken at eleven pre-determined gastric locations. High resolution pHmetry (12 sensors at 11 mm intervals) and manometry (36 sensors at 7.5 mm intervals) was performed fasted and after a standardised meal. The position of the squamocolumnar junction, marked with two endoscopically placed radio-opaque clips, was visualised radiologically relative to the probes. The biopsy specimens were scored for inflammation and stained with monoclonal antibody to H+/K+ATPase for counting parietal cell (PC) density. Results In the fasting period, at all sensors more than 1.1 cm below the peak LES pressure the median pH was less acidic in H. pylori positives (Table 1). After a meal, intragastric acidity was less in H. pylori positives compared to negatives at sensors 2.2 to 4.4 cm below the peak LES pressure (all p < 0.05), which are the sensors closest to the gastroesophageal junction (GOJ). Median PC density (IQR) at mid-greater curve of gastric body was 233 (96) for H. pylori positives and 352 (76) for negatives (p < 0.001). PC density was lower in H. pylori positives in 10 out of the 11 gastric locations (all p < 0.01). Positive CagA status was associated with reduced intragastric acidity, but had no effect on PC density or mucosal inflammation when compared to CagA negative H. pylori positives.Abstract PWE-071 Table 1 Median pH (IQR) detected by sensors relative to the peak LES pressure during the 20 minute fasting period H.pylori negative H.pylori positive Sensor location Median pH (IQR) 1.1 cm proximal 7.33 (0.78) 7.37 (0.62) PeakLES pressure 7.34 (0.79) 7.28 (0.51) 1.1 cm distal 7.06 (1.63) 7.13 (0.51) 2.2 cm distal 5.79 (4.26) 6.94 (1.38) * 3.3 cm distal 2.27 (2.58) 6.13 (5.06) ** 4.4 cm distal 1.70 (1.16) 4.11 (4.95) ** 5.5 cm distal 1.68 (0.66) 2.88 (3.66) ** 6.6 cm distal 1.62 (3.66) 2.39 (3.06) * *p < 0.01,**p < 0.001 Conclusion The majority of H. pylori infected subjects have reduced intragastric acidity and PC density compared to the uninfected population and the reduction in acidity is most marked close to the GOJ. This may explain the negative association between H. pylori infection and both gastroesophageal reflux disease and oesophageal adenocarcinoma. Disclosure of Interest None Declared