Inflammatory gradient in Barrett's oesophagus: implications for disease complications.

INTRODUCTION: Barrett's oesophageal epithelium (BE) is clinically important due to the associated inflammatory and malignant complications which are unevenly distributed throughout the BE segment. As the immunoregulatory environment may influence disease manifestations, we analysed the inflammatory and cytokine responses throughout the BE mucosa. We then investigated whether the inflammatory gradient is related to the distribution of metaplastic cell subtypes, epithelial exposure to the components of refluxate, or squamocolumnar cell interactions. METHODS: Fifty consecutive patients with long segment BE were recruited. The segmental degree of endoscopic and histopathological inflammation was graded, and expression of interleukin (IL)-1 beta, IL-8, IL-4, and IL-10 were determined by ELISA following organ culture with or without addition of acid or bile salts. Mucin staining and IL-10 immunohistochemistry were performed. The effect of squamocolumnar interactions on cytokine expression were analysed using cocultures of squamous (OE-21) and BE (TE7) carcinoma cell lines. RESULTS: There was a histopathological inflammatory gradient in BE. Inflammation was maximal at the new squamocolumnar junction with > or = 2-fold increase in proinflammatory IL-8 and IL-1 beta expression. The proximal proinflammatory response could not be explained by the distribution of metaplastic subtypes. Pulsatile exposure of BE to acid and bile, as well as juxtaposition of BE to squamous epithelial cells in culture, increased expression of IL-1 beta. In contrast, inflammation was minimal distally with a significant increase in anti-inflammatory IL-10 expression and 4/6 cancers occurred distally. CONCLUSIONS: Specific cytokine responses may contribute to the localisation of inflammatory and malignant complications within BE.

Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants.

BACKGROUND AND AIMS: Approximately 10% of adults experience gastro-oesophageal reflux symptoms with a variable oesophageal response. A total of 60% have no endoscopic abnormality, 30% have oesophagitis, and 10% have Barrett's oesophagus. We investigated whether the inflammatory cell infiltrate and cytokine profiles of these clinical phenotypes merely vary in severity or are fundamentally different. METHODS: Patients with reflux symptoms and a normal oesophagus (n=18), oesophagitis (n=26), and Barrett's oesophagus (n=22 newly diagnosed, n=28 surveillance) were recruited. Endoscopic and histopathological degrees of inflammation were scored. Cytokine expression was determined by competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: In oesophagitis, endoscopic and histopathological grades of inflammation correlated highly. mRNA expression of proinflammatory interleukin (IL)-1beta, IL-8, and interferon gamma (IFN-gamma) were increased 3-10-fold compared with non-inflamed squamous or Barrett's oesophageal samples. There was a modest increase in anti-inflammatory IL-10 but no increase in IL-4. In Barrett's oesophagus, 29/50 had no endoscopic evidence of inflammation and histopathological inflammation was mild in 17/50 and moderate in 24/50, independent of acid suppressants. Expression of IL-1beta, IL-8, and IFN-gamma was similar to non-inflamed squamous mucosa. IL-10 was increased 1.6-fold similar to oesophagitis. IL-4 was increased fourfold, with 100-fold increase in IL-4/T cell receptor expression, compared with squamous oesophagus or oesophagitis. CONCLUSIONS: Barrett's oesophagus is characterised by a distinct Th-2 predominant cytokine profile compared with the proinflammatory nature of oesophagitis. The specific oesophageal immune responses may influence disease development and progression.

Rigorous surveillance protocol increases detection of curable cancers associated with Barrett's esophagus.

Esophageal adenocarcinoma is increasing in incidence and has a high mortality unless detected early. Barrett's esophagus is the only known risk factor for this cancer; however, whether endoscopic surveillance reduces morbidity and mortality is controversial. Endoscopic cancer surveillance programes for Barrett's esophagus are not routinely practiced in the UK, and this is the first study to examine whether a rigorous surveillance protocol increases the detection rate of early oesophageal cancer. All patients with a diagnosis of Barrett's esophagus or associated adenocarcinoma attending Havering Hospitals NHS Trust between 1992 and 1998 were included. A retrospective analysis was made of patients undergoing informal surveillance (96 patients, 1992-1997) and a prospective analysis was conducted following the implementation of a rigorous protocol (108 patients, 1997-1998). Over the same time periods Barrett's associated cancers diagnosed in patients not undergoing surveillance were analyzed (262 patients 1992-1997, 98 patients 1997-1998). From 1992 to 1997, one case of high-grade dysplasia was detected (N = 96, 1%). From 1997 to 1998, two cancers and three high-grade dysplasias were detected during rigorous surveillance (N = 108, 4.6%). Three of these patients have had curative esophagectomies (one high-grade dysplasia and two T1,N0,M0 tumors). In 1992-1997, 10 patients were found to have cancer in previously undiagnosed Barrett's esophagus (N = 262, 3.8%). Of 3/10 cancers treated surgically, one patient had a curative procedure (T1,N0,M0). In 1997-1998, nine patients were found to have de novo Barrett's esophagus cancer (N = 88, 10.2%) and three had curative resections (T1,N0,M0). Two of the patients with T1 lesions had no endoscopic evidence of cancer but were detected as a result of the multiple biopsy protocol. In conclusion, a rigorous biopsy protocol increases the detection of early cancer in Barrett's esophagus.

Fundal gastritis as a potential cause of reflux oesophagitis.

The transient lower oesophageal sphincter relaxations which allow reflux may be due to altered afferent pathways from the fundus. We aimed to determine whether fundal inflammation is the underlying cause. Two endoscopic biopsies were taken from each of the gastric antrum and fundus in 25 asymptomatic controls with a normal endoscopy (median age 54 range 13-83 years), and 33 patients with erosive oesophagitis (median age 52, 11-78 years). No patient had taken acid suppression therapy or antibiotics for at least 1 month. Sections were stained with haematoxylin and eosin and Giemsa stain and examined in a blinded fashion by one pathologist for the presence of gastritis (Sydney classification) and Helicobacter pylori. Chronic gastritis was common in both groups, but was usually mild. In Helicobacter pylori-negative subjects, there was significantly less chronic gastritis in the antrum and the fundus in oesophagitis patients than in controls (p < 0.05). When present, gastric atrophy was usually antral and mild in severity. There was no difference in the incidence of gastric atrophy in patients with oesophagitis compared with controls (24% compared with 40%; p > 0.05). Chronic gastritis is not more common in patients with oesophagitis, and is unlikely to play a part in the pathogenesis of this disease.

APACHE II scores and deaths after upper gastrointestinal endoscopy in hospital inpatients.

Advanced age and comorbidity as well as gastrointestinal (GI) disease contribute to the increased mortality after upper GI endoscopy in inpatients when compared to outpatients. The aim of this study was to measure comorbidity in inpatients undergoing endoscopy using the Acute Physiology and Chronic Health Evaluation (APACHE) II severity of disease classification and to assess the usefulness of the APACHE II system in predicting outcome. During a 10-week period, 155 consecutive inpatients undergoing upper GI endoscopy were prospectively scored using APACHE II. They were followed up for 30 days, the measured endpoint being death. Of these, 92 (59%) inpatients were admitted with GI hemorrhage, 14 (9%) were admitted for other reasons but subsequently bled, and 49 (32%) were endoscoped for reasons other than bleeding. The mean (SEM) APACHE II score in patients with GI bleeding was 8.0 (0.5), and in patients without bleeding was 6.5 (0.6; p = 0.07). Eighteen patients (12%) died within 30 days of endoscopy. APACHE scores were higher at 10.5 (1.2) in patients who died, compared to 7.1 (0.4) in those who lived (p < 0.01). Increased acute physiology scores led to this difference. Age and chronic health scores were similar in both groups. In the 18 patients who died, 9 had GI bleeding and their mean APACHE score was 13.8 (1.5); 9 had been endoscoped for other reasons and had a lower score of 7.2 (1.3; p < 0.01). These latter 9 deaths amounted to a 18% mortality in the nonbleeding group, which was greater than expected. APACHE II scores can help predict poor outcome in inpatients referred for endoscopy. However, the APACHE II system has limitations and failed to identify (by means of a high score) some patients without GI bleeding who subsequently died. A tool to measure comorbidity, such as the APACHE II system, is necessary when comparing groups of patients in different settings.

Morbidity, mortality, and risk factors for esophagitis in hospital inpatients.

Esophagitis is a common endoscopic finding, although its prevalence and contribution to morbidity and mortality in hospital inpatients has not been systematically evaluated. This study aimed to determine the prevalence of esophagitis among hospital inpatients referred for upper gastrointestinal endoscopy, to assess factors associated with the presence of esophagitis, and to determine the mortality of patients with esophagitis. All inpatients referred for upper gastrointestinal endoscopy in a district general hospital were assessed prospectively for one year. The reason for referral, endoscopy findings, and one-month mortality were determined together with a history of nasogastric intubation, periods spent supine, and drug use. Of 595 inpatients who underwent gastroscopy, 58% were referred for investigation of acute upper gastrointestinal bleeding. Esophagitis was found in 196 (33%). Esophagitis was significantly associated with wide-bore nasogastric intubation (p = 0.021; relative risk, 2.61; 95% CI, 0.64-6.06) but not with fine-bore nasogastric intubation. Esophagitis was also significantly associated with being nursed supine (p = 0.015; relative risk, 1.41; 95% CI, -1.75-6.72). There was no association between esophagitis and specific drug therapy. Mortality among patients with esophagitis was higher than those without esophagitis (p = 0.04; relative risk, 1.38; 95% CI, 0.34-3.22). Reflux esophagitis is common in hospital inpatients who are endoscoped. Although the underlying diseases are likely to account for the high mortality, the associations of wide-bore nasogastric intubation and being nursed supine should alert caregivers to an increased risk. If nasogastric intubation is required for feeding only, fine-bore tubes should be considered.

Gastric compliance, sensation, and the relaxation response to a nitric oxide donor in health and reflux oesophagitis.

BACKGROUND/AIMS: The gastric fundus affects afferent control of lower oesophageal sphincter function. Nitric oxide is an important relaxant of the fundus. We postulated that gastric distensibility, compliance and nitric oxide sensitivity may be altered in patients with gastro-oesophageal reflux disease (GERD). METHODS: 9 patients with erosive oesophagitis (6 males; median age 55 years) and 16 healthy controls (9 males; median age 36 years) were studied fasting with a gastric barostat. Minimal distending pressure (MDP) and gastric compliance (Deltav/Deltap) were determined by increasing intrabag pressure in 2-mm Hg increments. The pressures required to produce initial sensation and maximum tolerated sensation were recorded. With the intrabag pressure set at MDP +2 mm Hg, 500 microg sublingual glyceryl trinitrate was administered and the percentage change in intrabag volume from initial volume recorded. RESULTS: The MDP was significantly greater in patients than controls (7.5 vs. 6.7 mm Hg median; p = 0.02). Gastric compliance was similar in both groups (57.8 vs. 67.2 ml/mm Hg; p = 0.4). There was no difference between groups in the pressure at first intragastric sensation (11.2 vs. 10.3 mm Hg above MDP; p = 0.5) or in the maximal tolerated pressure (15.8 vs. 14.3 mm Hg above MDP; p = 0.2). The proportional change in gastric volume from baseline in response to glyceryl trinitrate was smaller in patients than controls (66 (3-200) vs. 120 (26-1,053)%; p = 0.02). CONCLUSIONS: Gastric MDP may be altered in GERD, but gastric compliance and sensitivity to distension are normal. Major gastric relaxation occurs in response to a nitric oxide donor, but this appears to be diminished in patients with GERD. Upper gut nitrinergic mechanisms may be altered in oesophageal reflux disease.

Development and application of endoloops for the treatment of bleeding esophageal varices.

BACKGROUND: Endoloops are detachable nylon snares. The aims of this study were to develop an endoscopic method for repeated delivery of endoloops to arrest variceal bleeding, to compare efficacy of endoloop hemostasis with injection and band ligation in experimental models of bleeding, and to test the reliability and safety of endoloops in a pilot study in patients with varices. METHODS: Technical modifications including ridged endcaps and alterations in angulation of endoloops were developed to speed delivery and improve efficacy. Hemostatic efficacy of endoloops was compared with sclerotherapy and band ligation in animal studies before studies in patients. RESULTS: Modified endcap and endoloops allowed repeated applications without withdrawal of the endoscope. Right-angled endoloops ensnared more (p < 0.0001) gastric tissue and were more reliable (p < 0.05) than straight endoloops. Injection therapy and prestretched bands appeared ineffective, whereas band ligation was only effective on vessels up to 2 mm in diameter. Only endoloops achieved hemostasis on vessels of 3 to 5 mm (p < 0.05). No significant complications occurred using endoloops in animal (esophagus n = 20, stomach n = 20) or human (n = 11) studies. CONCLUSIONS: Endcap and endoloop modifications simplified repeated application to varices. Endoloops were more effective than injection or band ligation in experimental hemostasis and appeared safe and effective in patients.

Oesophageal epithelial innervation in health and reflux oesophagitis.

BACKGROUND: The response of the oesophagus to refluxed gastric contents is likely to depend on intact neural mechanisms in the oesophageal mucosa. The epithelial innervation has not been systematically evaluated in health or reflux disease. AIMS: To study oesophageal epithelial innervation in controls, and also inflamed and non-inflamed mucosa in patients with reflux oesophagitis and healed oesophagitis. PATIENTS: Ten controls, nine patients with reflux oesophagitis, and five patients with healed oesophagitis. METHODS: Oesophageal epithelial biopsy specimens were obtained at endoscopy. The distribution of the neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), substance P (SP), and vasoactive intestinal peptide (VIP) were investigated by immunohistochemistry. Density of innervation was assessed by the proportion of papillae in each oesophageal epithelial biopsy specimen containing immunoreactive fibres (found in the subepithelium and epithelial papillae, but not penetrating the epithelium). RESULTS: The proportion of papillae positive for PGP immunoreactive nerve fibres was significantly increased in inflamed tissue when compared with controls, and non-inflamed and healed tissue. There was also a significant increase in VIP immunoreactive fibres within epithelial papillae. Other neuropeptides showed no proportional changes in inflammation. CONCLUSIONS: Epithelial biopsy specimens can be used to assess innervation in the oesophagus. The innervation of the oesophageal mucosa is not altered in non-inflamed tissue of patients with oesophagitis but alters in response to inflammation, where there is a selective increase (about three- to fourfold) in VIP containing nerves.

Symptomatic gastroesophageal reflux in acutely hospitalized patients.

Patients admitted acutely to hospital may be at risk of increased morbidity and mortality as a result of gastroesophageal reflux and its complications. The recognized association of gastroesophageal reflux with cardiac and respiratory disease, the use of drugs that reduce lower esophageal sphincter pressure, and the supine position in which many patients are nursed may increase the risk of gastroesophageal reflux. This study aimed to determine the prevalence and severity of refluxlike symptoms in a series of consecutive unselected patients admitted acutely through the accident and emergency department of a district general hospital and to study the effect of hospitalization on these symptoms. Patients were interviewed by questionnaire on two occasions: immediately following admission and again 7-10 days later. The frequency of symptoms of heartburn, acid regurgitation, dysphagia, nausea, and belching were recorded on a 6-point scale, in addition to whether these symptoms occurred at night. Medication history, the number of days spent on bed rest, nasogastric intubation, and operation history were also recorded. In all, 275 patients were interviewed, of whom 229 had a second interview; 27% (62) had symptoms at least once a week (49% reported symptoms at least once a month) prior to admission, of whom 4% (9) had daily heartburn and/or acid regurgitation. Following admission to hospital there was a significant (P < 0.001) fall in the prevalence and frequency of refluxlike symptoms. There was a significant association of refluxlike symptoms with number of days spent in bed (P < 0.05) and with the use of nonsteroidal antiinflammatory drugs in hospital (P < 0.0001). Logistic regression analysis confirmed the association of NSAIDs with refluxlike symptoms. Nasogastric intubation and surgery were not associated with heartburn. In conclusion, symptoms of heartburn and acid regurgitation become less frequent following admission to hospital. This probably relates to a reduction in physical exertion following hospital admission but may reflect a reduction in anxiety levels or treatment of underlying disease. Patients on prolonged bed rest and those given non-steroidal anti-inflammatory drugs are at increased risk of refluxlike symptoms and may require antireflux measures.

Do gastroenterologists want to be trained in ultrasound? A national survey of trainees in gastroenterology.

AIMS: (1) To establish whether gastroenterologists wish to train in abdominal ultrasound according to the Royal College of Radiologists' document, Guidance for the training in ultrasound of medical non-radiologists. (2) To determine whether the ultrasound workload generated by gastroenterologists differs from that by other clinicians. METHODS: A postal questionnaire was sent to all 278 gastroenterology trainees. The indications and findings of 100 consecutive gastroenterologist requested scans were compared with 100 scans requested sequentially by other clinicians through a teaching hospital radiology department. RESULTS: 82% of the survey forms were returned. 77% of trainees wished to train in abdominal ultrasound and 68% were prepared to train in the manner outlined in the guideline document. However, 86% felt that they would ideally prefer not to assess renal or pelvic pathology, restricting to hepatobiliary diagnosis only. 73% of trainees did not anticipate that a further scan by a radiologist would be required. Comparison of gastroenterology scans with those requested by other clinicians revealed a relative excess of hepatobiliary indications and findings, and a notable paucity of renal and pelvic pathology in gastroenterology practice. CONCLUSIONS: There is general interest in abdominal ultrasound training among gastroenterology trainees and broad acceptance of the guideline document. However, most trainees perceive a focus of training restricted to hepatobiliary disease to be most appropriate. The case mix study provides support for this viewpoint. It is suggested that a more focused ultrasound training for gastroenterologists be considered.

Speed of onset of oesophageal acid reduction with different proton-pump inhibitors in patients with reflux oesophagitis.

OBJECTIVE: Proton-pump inhibitors are the most effective drug treatment for gastro-oesophageal reflux disease. With the increasing trend toward 'on demand' therapy, it is important to determine how quickly oesophageal acid reflux is reduced, and whether this differs between the available compounds. DESIGN: A 2 x 2 double-blind crossover study. METHOD: Eight patients with Savary-Miller grade II oesophagitis underwent 24 h pre-treatment oesophageal pH monitoring. Each patient was randomly allocated to receive daily omeprazole 20 mg and lansoprazole 30 mg for 2 days, in two separate double-blind periods, with a washout period of 14 days. Two further oesophageal pH recordings were obtained during the second 48 h period of treatment with each drug. RESULTS: Five patients completed the study and their results are presented. Lansoprazole significantly reduced the percentage of total reflux time (P = 0.04) and percentage upright reflux time (P=0.04) on the second day of treatment compared to the pre-treatment, while this was not achieved with omeprazole. There was a significant difference in the reduction of the total reflux time (P= 0.011), upright reflux time (P=0.021) and total reflux episodes (P < 0.001) on day 2 of treatment when comparing lansoprazole with omeprazole. All patients on lansoprazole had a decrease in symptoms of heartburn and regurgitation, with complete resolution in four patients. Three patients had a decrease in these symptoms with omeprazole, including complete resolution in two. CONCLUSION: This study was limited by the small number of patients who underwent this demanding investigation. However, lansoprazole appears to have a more rapid onset of reduction of acid gastro-oesophageal reflux than omeprazole over a 48 h period.

Evaluation of Helicobacter pylori in reflux oesophagitis and Barrett's oesophagus.

BACKGROUND: One of the major pathophysiological abnormalities in patients with gastro-oesophageal reflux disease is thought to involve transient lower oesophageal sphincter (LOS) relaxations. One component of the neural mechanism controlling the LOS appears to be a reflex are whose afferent limb originates in the gastric fundus. As inflammation is known to be associated with neural activation an investigation was made to determine whether gastric infection with H pylori is altered in prevalence or distribution in patients with reflux disease. METHODS: Five groups of subjects referred for endoscopy-group 1: 25 controls (asymptomatic individuals with anaemia and normal endoscopy); group 2: 36 subjects with erosive oesophagitis alone (Savary-Millar grades I-III); group 3: 16 subjects with duodenal ulcer alone; group 4: 15 subjects with oesophagitis with duodenal ulcer; group 5: 16 subjects with Barrett's oesophagus. No patients were receiving acid suppressants or antibiotics. An antral biopsy specimen was taken for a rapid urease test, and two biopsy specimens were taken from the antrum, fundus, and oesophagus (inflamed and non-inflamed) for histological evidence of inflammation and presence of H pylori using a Giemsa stain. RESULTS: Nine (36%) controls had H pylori. Patients with duodenal ulcer alone had a significantly higher incidence of colonisation by H pylori than other groups (duodenal ulcer 15 (94%); oesophagitis 13 (36%); oesophagitis+duodenal ulcer 6 (40%); Barrett's oesophagus 4 (25%)). H pylori was not more common in oesophagitis. When H pylori colonised the gastric antrum it was usually found in the gastric fundus. There was no difference in anatomical distribution of H pylori in the different patient groups. In Barrett's oesophagus H pylori was found in two of 16 in the metaplastic epithelium. CONCLUSION: H pylori is not more common and its distribution does not differ in those with oesophagitis compared with control subjects, and is therefore unlikely to be aetiologically important in these patients. H pylori, however, can colonise Barrett's epithelium.