Francis Ka-Leung Chan

Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen

BACKGROUNDnMany patients who have had upper gastrointestinal bleeding continue to take low-dose aspirin for cardiovascular prophylaxis or other non-steroidal antiinflammatory drugs (NSAIDs) for musculoskeletal pain. It is uncertain whether infection with Helicobacter pylori is a risk factor for bleeding in such patients.nnnMETHODSnWe studied patients with a history of upper gastrointestinal bleeding who were infected with H. pylori and who were taking low-dose aspirin or other NSAIDs. We evaluated whether eradication of the infection or omeprazole treatment was more effective in preventing recurrent bleeding. We recruited patients who presented with upper gastrointestinal bleeding that was confirmed by endoscopy. Their ulcers were healed by daily treatment with 20 mg of omeprazole for eight weeks or longer. Then, those who had been taking aspirin were given 80 mg of aspirin daily, and those who had been taking other NSAIDs were given 500 mg of naproxen twice daily for six months. The patients in each group were then randomly assigned separately to receive 20 mg of omeprazole daily for six months or one week of eradication therapy, consisting of 120 mg of bismuth subcitrate, 500 mg of tetracycline, and 400 mg of metronidazole, all given four times daily, followed by placebo for six months.nnnRESULTSnWe enrolled 400 patients (250 of whom were taking aspirin and 150 of whom were taking other NSAIDs). Among those taking aspirin, the probability of recurrent bleeding during the six-month period was 1.9 percent for patients who received eradication therapy and 0.9 percent for patients who received omeprazole (absolute difference, 1.0 percent; 95 percent confidence interval for the difference, -1.9 to 3.9 percent). Among users of other NSAIDs, the probability of recurrent bleeding was 18.8 percent for patients receiving eradication therapy and 4.4 percent for those treated with omeprazole (absolute difference, 14.4 percent; 95 percent confidence interval for the difference, 4.4 to 24.4 percent; P=0.005).nnnCONCLUSIONSnAmong patients with H. pylori infection and a history of upper gastrointestinal bleeding who are taking low-dose aspirin, the eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Omeprazole is superior to the eradication of H. pylori in preventing recurrent bleeding in patients who are taking other NSAIDs.

Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers

BACKGROUNDnHelicobacter pylori infection is common in patients with peptic ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs). But the pathogenic role of H pylori in this disease is controversial. We studied the efficacy of eradication of H pylori in the prevention of NSAID-induced peptic ulcers.nnnMETHODSnWe recruited patients with musculoskeletal pain who required NSAID treatment. None of the patients had previous exposure to NSAID therapy. Patients who had H pylori infection but no pre-existing ulcers on endoscopy were randomly allocated naproxen alone (750 mg daily) for 8 weeks or a 1-week course of triple therapy (bismuth subcitrate 120 mg, tetracycline 500 mg, metronidazole 400 mg, each given orally four times daily) before administration of naproxen (750 mg daily). Endoscopy was repeated after 8 weeks of naproxen treatment or when naproxen treatment was stopped early because of bleeding or intractable dyspepsia. All endoscopic examinations were done by one endoscopist who was unaware of treatment assignment. The primary endpoint was the cumulative rate of gastric and duodenal ulcers.nnnFINDINGSn202 patients underwent endoscopic screening for enrolment in the trial, and 100 eligible patients were randomly assigned treatment. 92 patients completed the trial (47 in the naproxen group, 45 in the triple-therapy group). At 8 weeks, H pylori had been eradicated from no patients in the naproxen group and 40 (89%) in the triple-therapy group (p < 0.001). 12 (26%) naproxen-group patients developed ulcers: five had ulcer pain and one developed ulcer bleeding. Only three (7%) patients on triple therapy had ulcers, and two of these patients had failure of H pylori eradication (p = 0.01). Thus, 12 (26%) patients with persistent H pylori infection but only one (3%) with successful H pylori eradication developed ulcers with naproxen (p = 0.002).nnnINTERPRETATIONnEradication of H pylori before NSAID therapy reduces the occurrence of NSAID-induced peptic ulcers.

Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial

BACKGROUNDnGuidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase (COX 2) inhibitor or a non-steroidal anti-inflammatory drug (NSAID) with a proton-pump inhibitor (PPI). These two treatments have similar effectiveness, but they are insufficient for protection of patients at very high risk for ulcer bleeding. We aimed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs, combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding.nnnMETHODSn441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre, prospective, randomised, double-blind trial after admission to hospital with upper-gastrointestinal bleeding. Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative. All patients were given 200 mg celecoxib twice daily. 137 patients were randomly assigned to receive 20 mg esomeprazole twice daily (combined-treatment group), and 136 to receive a placebo (control group) for 12 months. The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00365313.nnnFINDINGSnCombination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk. The 13-month cumulative incidence of the primary endpoint was 0% in the combined-treatment group and 12 (8.9%) in the controls (95% CI difference, 4.1 to 13.7; p=0.0004). The median follow-up was 13 months (range 0.4-13.0). Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups.nnnINTERPRETATIONnPatients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI. Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding.

Asia Pacific consensus recommendations for colorectal cancer screening

Colorectal cancer (CRC) is rapidly increasing in Asia, but screening guidelines are lacking. Through reviewing the literature and regional data, and using the modified Delphi process, the Asia Pacific Working Group on Colorectal Cancer and international experts launch consensus recommendations aiming to improve the awareness of healthcare providers of the changing epidemiology and screening tests available. The incidence, anatomical distribution and mortality of CRC among Asian populations are not different compared with Western countries. There is a trend of proximal migration of colonic polyps. Flat or depressed lesions are not uncommon. Screening for CRC should be started at the age of 50 years. Male gender, smoking, obesity and family history are risk factors for colorectal neoplasia. Faecal occult blood test (FOBT, guaiac-based and immunochemical tests), flexible sigmoidoscopy and colonoscopy are recommended for CRC screening. Double-contrast barium enema and CT colonography are not preferred. In resource-limited countries, FOBT is the first choice for CRC screening. Polyps 5–9 mm in diameter should be removed endoscopically and, following a negative colonoscopy, a repeat examination should be performed in 10 years. Screening for CRC should be a national health priority in most Asian countries. Studies on barriers to CRC screening, education for the public and engagement of primary care physicians should be undertaken. There is no consensus on whether nurses should be trained to perform endoscopic procedures for screening of colorectal neoplasia.

Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography

Objective Knowledge of the epidemiology of non-alcoholic fatty liver disease (NAFLD) is incomplete because liver biopsy cannot be performed on the general population to assess disease severity. New non-invasive tests allow accurate and safe assessment in healthy individuals. The aim of this study was to examine the prevalence of NAFLD and advanced fibrosis in the general Hong Kong Chinese population. Methods Subjects were recruited from the community by random selection from the government census database. Liver fat and fibrosis were assessed by proton-magnetic resonance spectroscopy and transient elastography, respectively. Results Overall, 264 of 922 (28.6%) subjects had intrahepatic triglyceride content ≥5%. Excluding 12 subjects with significant alcohol consumption, the population prevalence of NAFLD was 27.3% (95% CI 24.5% to 30.2%). Each component of the metabolic syndrome increased the risk of fatty liver in a dose-dependent manner (prevalence of 4.5% in subjects without any component and 80.0% in those with all five components). 8 (3.7%) patients with fatty liver had liver stiffness ≥9.6u2005kPa, a level suggestive of advanced fibrosis. Body mass index and alanine aminotransferase level were independent factors associated with liver stiffness. Together with other clinical prediction scores, the estimated prevalence of advanced fibrosis in patients with fatty liver in the community was <10%. Compared with non-drinkers, modest drinkers (<10u2005g per day) did not have higher risk of fatty liver after adjustment for demographic and metabolic factors. The liver stiffness was 4.7±1.9u2005kPa in modest drinkers and 4.6±1.7u2005kPa in non-drinkers (p=0.54). Conclusion NAFLD is found in over a quarter of the general adult Chinese population, but the proportion of patients with advanced fibrosis is low. Modest alcohol consumption does not increase the risk of fatty liver or liver fibrosis.

Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease

Objective Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. Methods This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as ≥50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. Results Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31; 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01; 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87±22u2005weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). Conclusions In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease.

Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

BACKGROUND & AIMSnBy using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer.nnnMETHODSnMethylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis.nnnRESULTSnPCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients.nnnCONCLUSIONSnPCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

Identification of Chronic Hepatitis B Patients without Significant Liver Fibrosis by a Simple Noninvasive Predictive Model

OBJECTIVE:Histological assessment of liver fibrosis is important in the management of chronic hepatitis B (CHB) infection but poorly accepted by patients because of its invasiveness. The aim of this study was to develop a noninvasive model to assess liver fibrosis in CHB patients using clinical and routine laboratory data.PATIENTS AND METHODS:This was a retrospective study on 235 treatment-naïve viremic CHB patients. Univariate analysis of data from the training cohort (n = 150) followed by multivariate logistic regression were performed to identify independent predictors of significant fibrosis and generate predictive models. The models were validated with the remaining patients or validation cohort (n = 85) and by receiver operating characteristics (ROC) analysis.RESULTS:Body mass index (BMI), platelet count, serum albumin, and total bilirubin levels were identified as independent predictors of bridging fibrosis or cirrhosis (Ishak stage 3–6). ROC analysis was performed using the predictive probabilities derived from the regression models. The area under the ROC curve of the best model was 0.803 (95% CI: 0.729–0.878) for the training cohort, 0.765 (95% CI: 0.644–0.885) for the validation cohort, and 0.791 (95% CI: 0.728–0.854) for the entire cohort. Using the low cut-off probability of 0.15, significant fibrosis could be excluded in 83 patients of the total patient population (negative predictive value 0.92).CONCLUSIONS:Our noninvasive model comprising BMI and three routine laboratory tests was accurate in predicting absence of significant fibrosis. Application of this model could provide useful additional information on the stage of disease, guide future management decisions, and potentially decrease the need for liver biopsy in some CHB patients.

High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B.

Increased interleukin‐6 (IL‐6) production is implicated in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. Although previous studies showed that HCC patients had higher serum IL‐6 level at the time of diagnosis, it is unclear if the cytokine contributes to the development of HCC or is just a reaction to cancer. To address this question, we performed a nested case‐control study. Consecutive chronic hepatitis B patients were recruited from 1997 to 2000 and followed till 2008. Profiling of 27 cytokines, chemokines and growth factors was performed at baseline, date of peak alanine aminotransferase (ALT) level and the last visit. Thirty‐seven patients developed HCC at a median follow‐up of 62 months (interquartile range: 41–110). Serum IL‐6 was higher in patients with HCC than controls both during peak ALT and at the last visit (both p = 0.02). Patients with IL‐6 above 7 pg/ml during peak ALT had increased risk of HCC or death (adjusted hazard ratio 3.0; 95% confidence interval 1.2, 7.8; p = 0.02). The sensitivity, specificity, positive and negative predictive values of this cutoff to predict future HCC development were 70%, 73%, 72% and 71%, respectively. Combination of IL‐6 and AFP improved the sensitivity in diagnosing HCC or predicting future HCC development. In conclusion, high serum IL‐6 level predates the development of HCC in chronic hepatitis B patients, and has moderate accuracy in predicting future cancer. This may assist clinicians in selecting high‐risk patients for HCC surveillance program.

Asia-Pacific consensus on the management of gastroesophageal reflux disease: update.

Background and Aims:u2002 Since the publication of the Asia‐Pacific GERD consensus in 2004, more data concerning the epidemiology and management of gastroesophageal reflux disease (GERD) have emerged. An evidence based review and update was needed.