Iain A. Murray

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.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

Background & Aims Barretts esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barretts and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Management of minor upper gastrointestinal haemorrhage in the community using the Glasgow Blatchford Score

Background The Glasgow Blatchford Score (GBS) is a validated risk assessment tool in primary upper gastrointestinal haemorrhage, which accurately predicts the need for intervention (endoscopic therapy, blood transfusion or surgery) or death. Aims To identify the GBS that predicts lack of intervention or death and to apply this to clinical practice by managing low-risk patients in the community. Methods GBSs prospectively calculated on 232 patients with upper gastrointestinal haemorrhage to identify low-risk score. Patients with low-risk of requiring intervention (GBS ≤2, age <70 years) from a further 304 patients were considered for management in the community. Results Fifty-two of 232 patients in the first cohort had a GBS ≤2 and were aged less than 70 years: none of these required intervention or died. In the second cohort 104 of 304 (34.2%) patients had a GBS ≤2 and were aged less than 70 years, none of whom died or required endoscopic therapy, blood transfusion, surgery or died. Thrity-two of 104 (10.5% of total cohort) were safely managed in the community. Conclusion Using the criteria of a GBS ≤2, aged less than 70 years to define patients at ‘low risk’ allows 10.5% of patients with primary upper gastrointestinal haemorrhage to be safely managed in the community.

Comparison of risk scoring systems for patients presenting with upper gastrointestinal bleeding: international multicentre prospective study

Objective To compare the predictive accuracy and clinical utility of five risk scoring systems in the assessment of patients with upper gastrointestinal bleeding. Design International multicentre prospective study. Setting Six large hospitals in Europe, North America, Asia, and Oceania. Participants 3012 consecutive patients presenting over 12 months with upper gastrointestinal bleeding. Main outcome measures Comparison of pre-endoscopy scores (admission Rockall, AIMS65, and Glasgow Blatchford) and post-endoscopy scores (full Rockall and PNED) for their ability to predict predefined clinical endpoints: a composite endpoint (transfusion, endoscopic treatment, interventional radiology, surgery, or 30 day mortality), endoscopic treatment, 30 day mortality, rebleeding, and length of hospital stay. Optimum score thresholds to identify low risk and high risk patients were determined. Results The Glasgow Blatchford score was best (area under the receiver operating characteristic curve (AUROC) 0.86) at predicting intervention or death compared with the full Rockall score (0.70), PNED score (0.69), admission Rockall score (0.66, and AIMS65 score (0.68) (all P<0.001). A Glasgow Blatchford score of ≤1 was the optimum threshold to predict survival without intervention (sensitivity 98.6%, specificity 34.6%). The Glasgow Blatchford score was better at predicting endoscopic treatment (AUROC 0.75) than the AIMS65 (0.62) and admission Rockall scores (0.61) (both P<0.001). A Glasgow Blatchford score of ≥7 was the optimum threshold to predict endoscopic treatment (sensitivity 80%, specificity 57%). The PNED (AUROC 0.77) and AIMS65 scores (0.77) were best at predicting mortality, with both superior to admission Rockall score (0.72) and Glasgow Blatchford score (0.64; P<0.001). Score thresholds of ≥4 for PNED, ≥2 for AIMS65, ≥4 for admission Rockall, and ≥5 for full Rockall were optimal at predicting death, with sensitivities of 65.8-78.6% and specificities of 65.0-65.3%. No score was helpful at predicting rebleeding or length of stay. Conclusions The Glasgow Blatchford score has high accuracy at predicting need for hospital based intervention or death. Scores of ≤1 appear the optimum threshold for directing patients to outpatient management. AUROCs of scores for the other endpoints are less than 0.80, therefore their clinical utility for these outcomes seems to be limited. Trial registration Current Controlled Trials ISRCTN16235737.

The management of low-risk primary upper gastrointestinal haemorrhage in the community: a 5-year observational study.

Background Acute upper gastrointestinal haemorrhage is a common medical emergency, initially managed with inpatient care. Bleeding stops spontaneously in over 80% of cases, indicating that patients with low-risk upper gastrointestinal haemorrhage may be more optimally managed in the community, without the need for admission to hospital. Aim To assess the safety of managing patients with low-risk upper gastrointestinal haemorrhage without admission to hospital. Methods Prospective/retrospective study of all patients presenting to a UK teaching hospital with low-risk upper gastrointestinal haemorrhage who were managed without admission to hospital over 5 years. Low risk was defined as Glasgow Blatchford Score of 2 or less, age below 70 years, no other active medical problems, not taking warfarin and suspected nonvariceal bleed. Outcome measures were the need for intervention (blood transfusion, endoscopic therapy or surgery) and death. Results One hundred and forty-two patients fulfilled the inclusion criteria, and were managed without admission to hospital. No patients required endoscopic intervention, blood transfusion or surgery. The 28-day mortality was nil. Forty-one patients had normal endoscopic examination and 11 had significant endoscopic findings (peptic ulceration=10, oozing Mallory–Weiss tear=1) but did not require intervention. Conclusion Patients presenting with a primary upper gastrointestinal haemorrhage aged below 70 years with a Glasgow Blatchford Score of 2 or less are at a low risk, and can be safely managed in the community.

Intestinal Disaccharidase Deficiency Without Villous Atrophy May Represent Early Celiac Disease

BACKGROUND Intestinal disaccharidase activities are decreased in untreated celiac disease and also in other conditions without villous atrophy. Of 908 patients examined for suspected malabsorption, 37 (4.1%) had generalized disaccharidase deficiency without villous atrophy. The aim was to determine if generalized disaccharidase deficiency without villous atrophy represented latent celiac disease. METHODS Case notes and histology of the 37 patients were reviewed. History and blood investigations including antigliadin and endomysial antibodies were checked. Where celiac disease was suspected, endoscopic duodenal biopsies for histology and disaccharidase estimation were repeated. RESULTS Of the initial 37 patients, 6 patients had had repeat endoscopic biopsies; one having celiac disease. A further 18 patients were reviewed. The remainder declined further investigation. Eight had repeat endoscopic duodenal biopsies; one had celiac disease. Two with positive celiac serology also had enteroscopy with jejunal biopsies; both had celiac disease. CONCLUSIONS At least 11% of patients with generalized disaccharidase deficiency without villous atrophy develop celiac disease. Enteroscopic biopsies from distal duodenum and proximal jejunum should be considered as the next investigation if endomysial or antigliadin antibodies are positive.Background: Intestinal disaccharidase activities are decreased in untreated celiac disease and also in other conditions without villous atrophy. Of 908 patients examined for suspected malabsorption, 37 (4.1%) had generalized disaccharidase deficiency without villous atrophy. The aim was to determine if generalized disaccharidase deficiency without villous atrophy represented latent celiac disease. Methods: Case notes and histology of the 37 patients were reviewed. History and blood investigations including antigliadin and endomysial antibodies were checked. Where celiac disease was suspected, endoscopic duodenal biopsies for histology and disaccharidase estimation were repeated. Results: Of the initial 37 patients, 6 patients had had repeat endoscopic biopsies; one having celiac disease. A further 18 patients were reviewed. The remainder declined further investigation. Eight had repeat endoscopic duodenal biopsies; one had celiac disease. Two with positive celiac serology also had enteroscopy with jejunal biopsies; both had celiac disease. Conclusions: At least 11% of patients with generalized disaccharidase deficiency without villous atrophy develop celiac disease. Enteroscopic biopsies from distal duodenum and proximal jejunum should be considered as the next investigation if endomysial or antigliadin antibodies are positive.

Clinical and laboratory features and natural history of seronegative hepatitis in a nontransplant centre.

Background Seronegative hepatitis is a recognized cause of liver failure requiring transplantation. The aetiology is unknown, but might relate to an unidentified virus or immune dysregulation. There are few data on seronegative hepatitis presenting to nontransplant centres. Objectives To describe the clinical/laboratory features and natural history of seronegative hepatitis and compare these with viral/autoimmune hepatitis. Methods Cases of seronegative, viral and autoimmune hepatitis were identified from 2080 consecutive patients attending a rapid-access jaundice clinic over a 14-year period. Results Of 881 patients with hepatocellular jaundice, 27 (3%) had seronegative hepatitis, 44 (5%) autoimmune and 62 (7%) viral hepatitis (acute hepatitis A, B, C and E viruses). Fifteen out of 27 (56%) patients with seronegative hepatitis were male, median age 60 years (range 14–74). Peak bilirubin was 63 &mgr;mol/l (range 9–363), alanine aminotransferase 932 IU/l (range 503–3807). Duration of illness was 7 weeks (range 4–12). No patients developed liver failure or had further bouts of hepatitis. One patient developed acute lymphoblastic leukaemia shortly after presentation. There was no difference in age/sex of patients with seronegative hepatitis and those with viral hepatitis. Compared with autoimmune hepatitis (age 65 years, range 15–91), patients with seronegative hepatitis were younger (P=0.002) and more likely to be male (P=0.004). Patients with autoimmune hepatitis were more likely (P<0.0001) to have an albumin less than 35 g/l, international normalized ratio greater than 1.2, raised IgG and positive antinuclear/smooth muscle antibody, compared with patients with seronegative hepatitis. Conclusion Seronegative hepatitis presenting to a nontransplant centre is generally a self-limiting illness. The aetiology is more likely to be viral than autoimmune.

Predictive value of symptoms and demographics in diagnosing malignancy or peptic stricture

AIM To determine which features of history and demographics predict a diagnosis of malignancy or peptic stricture in patients presenting with dysphagia. METHODS A prospective case-control study of 2000 consecutive referrals (1031 female, age range: 17-103 years) to a rapid access service for dysphagia, based in a teaching hospital within the United Kingdom, over 7 years. The service consists of a nurse-led telephone triage followed by investigation (barium swallow or gastroscopy), if appropriate, within 2 wk. Logistic regression analysis of demographic and clinical variables was performed. This includes age, sex, duration of dysphagia, whether to liquids or solids, and whether there are associated features (reflux, odynophagia, weight loss, regurgitation). We determined odds ratio (OR) for these variables for the diagnoses of malignancy and peptic stricture. We determined the value of the Edinburgh Dysphagia Score (EDS) in predicting cancer in our cohort. Multivariate logistic regression was performed and P < 0.05 considered significant. The local ethics committee confirmed ethics approval was not required (audit). RESULTS The commonest diagnosis is gastro-esophageal reflux disease (41.3%). Malignancy (11.0%) and peptic stricture (10.0%) were also relatively common. Malignancies were diagnosed by histology (97%) or on radiological criteria, either sequential barium swallows showing progression of disease or unequivocal evidence of malignancy on computed tomography. The majority of malignancies were esophago-gastric in origin but ear, nose and throat tumors, pancreatic cancer and extrinsic compression from lung or mediastinal metastatic cancer were also found. Malignancy was statistically more frequent in older patients (aged >73 years, OR 1.1-3.3, age < 60 years 6.5%, 60-73 years 11.2%, > 73 years 11.8%, P < 0.05), males (OR 2.2-4.8, males 14.5%, females 5.6%, P < 0.0005), short duration of dysphagia (≤ 8 wk, OR 4.5-20.7, 16.6%, 8-26 wk 14.5%, > 26 wk 2.5%, P < 0.0005), progressive symptoms (OR 1.3-2.6: progressive 14.8%, intermittent 9.3%, P < 0.001), with weight loss of ≥ 2 kg (OR 2.5-5.1, weight loss 22.1%, without weight loss 6.4%, P < 0.0005) and without reflux (OR 1.2-2.5, reflux 7.2%, no reflux 15.5%, P < 0.0005). The likelihood of malignancy was greater in those who described true dysphagia (food or drink sticking within 5 s of swallowing than those who did not (15.1% vs 5.2% respectively, P < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the EDS were 98.4%, 9.3%, 11.8% and 98.0% respectively. Three patients with an EDS of 3 (high risk EDS ≥ 3.5) had malignancy. Unlike the original validation cohort, there was no difference in likelihood of malignancy based on level of dysphagia (pharyngeal level dysphagia 11.9% vs mid sternal or lower sternal dysphagia 12.4%). Peptic stricture was statistically more frequent in those with longer duration of symptoms (> 6 mo, OR 1.2-2.9, ≤ 8 wk 9.8%, 8-26 wk 10.6%, > 26 wk 15.7%, P < 0.05) and over 60 s (OR 1.2-3.0, age < 60 years 6.2%, 60-73 years 10.2%, > 73 years 10.6%, P < 0.05). CONCLUSION Malignancy and peptic stricture are frequent findings in those referred with dysphagia. The predictive value for associated features could help determine need for fast track investigation whilst reducing service pressures.

The natural history of autoimmune hepatitis presenting with jaundice.

Background Forty percent of patients with autoimmune hepatitis (AIH) present with acute jaundice/hepatitis. Such patients, when treated promptly, are thought to have a good prognosis. Objectives The objective of this study was to describe the natural history of AIH in patients presenting with jaundice/hepatitis and to determine whether the diagnosis could have been made earlier, before presentation. Methods This study is a retrospective review of 2249 consecutive patients who presented with jaundice to the Jaundice Hotline clinic, Truro, Cornwall, UK, over 15 years (1998–2013) and includes a review of the laboratory data over a 23-year period (1990–2013). Results Of the 955 patients with hepatocellular jaundice, 47 (5%) had criterion-referenced AIH: 35 female and 12 male, the median age was 65 years (range 15–91 years); the bilirubin concentration was 139 &mgr;mol/l (range 23–634 &mgr;mol/l) and the alanine transaminase level was 687 IU/l (range 22–2519 IU/l). Among the patients, 23/46 (50%) were cirrhotic on biopsy; 11/47 (23%) died: median time from diagnosis to death, 5 months (range 1–59); median age, 72 years (range 59–91 years). All 8/11 patients who died of liver-related causes were cirrhotic. Weight loss (P=0.04) and presence of cirrhosis (P=0.004) and varices (P=0.015) were more common among those who died. Among patients who died from liver-related causes, 6/8 (75%) died less than 6 months from diagnosis. Cirrhosis at presentation and oesophageal varices were associated with early liver-related deaths (P=0.011, 0.002 respectively). Liver function test results were available in 33/47 (70%) patients before presentation. Among these patients, 16 (49%) had abnormal alanine transaminase levels previously, and eight (50%) were cirrhotic at presentation. Conclusion AIH presenting as jaundice/hepatitis was mainly observed in older women: 50% of the patients were cirrhotic, and liver-related mortality was high. Some of these deaths were potentially preventable by earlier diagnosis, as the patients had abnormal liver function test results previously, which had not been investigated.

Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial

Summary Background Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barretts oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barretts oesophagus. Methods The Aspirin and Esomeprazole Chemoprevention in Barretts metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barretts oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barretts oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77. Findings Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events. Interpretation High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barretts oesophagus. Funding Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.