Joseph Jao Yiu Sung

International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding

DESCRIPTION A multidisciplinary group of 34 experts from 15 countries developed this update and expansion of the recommendations on the management of acute nonvariceal upper gastrointestinal bleeding (UGIB) from 2003. METHODS The Appraisal of Guidelines for Research and Evaluation (AGREE) process and independent ethics protocols were used. Sources of data included original and published systematic reviews; randomized, controlled trials; and abstracts up to October 2008. Quality of evidence and strength of recommendations have been rated by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RECOMMENDATIONS Recommendations emphasize early risk stratification, by using validated prognostic scales, and early endoscopy (within 24 hours). Endoscopic hemostasis remains indicated for high-risk lesions, whereas data support attempts to dislodge clots with hemostatic, pharmacologic, or combination treatment of the underlying stigmata. Clips or thermocoagulation, alone or with epinephrine injection, are effective methods; epinephrine injection alone is not recommended. Second-look endoscopy may be useful in selected high-risk patients but is not routinely recommended. Preendoscopy proton-pump inhibitor (PPI) therapy may downstage the lesion; intravenous high-dose PPI therapy after successful endoscopic hemostasis decreases both rebleeding and mortality in patients with high-risk stigmata. Although selected patients can be discharged promptly after endoscopy, high-risk patients should be hospitalized for at least 72 hours after endoscopic hemostasis. For patients with UGIB who require a nonsteroidal anti-inflammatory drug, a PPI with a cyclooxygenase-2 inhibitor is preferred to reduce rebleeding. Patients with UGIB who require secondary cardiovascular prophylaxis should start receiving acetylsalicylic acid (ASA) again as soon as cardiovascular risks outweigh gastrointestinal risks (usually within 7 days); ASA plus PPI therapy is preferred over clopidogrel alone to reduce rebleeding.

Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Accurate noninvasive tests for liver injury are urgently needed. The aim of this study was to evaluate the accuracy of transient elastography for the diagnosis of fibrosis and cirrhosis in patients with NAFLD and to study factors associated with discordance between transient elastography and histology. Two hundred forty‐six consecutive patients from two ethnic groups had successful liver stiffness measurement and satisfactory liver biopsy specimens. The area under the receiver‐operating characteristics curve (AUROC) of transient elastography for F3 or higher and F4 disease was 0.93 and 0.95, respectively, and was significantly higher than that of the aspartate aminotransferase–to–alanine aminotransferase ratio, aspartate aminotransferase–to–platelet ratio index, FIB‐4, BARD, and NAFLD fibrosis scores (AUROC ranged from 0.62 to 0.81, P < 0.05 for all comparisons). At a cutoff value of 7.9 kPa, the sensitivity, specificity, and positive and negative predictive values for F3 or greater disease were 91%, 75%, 52%, and 97%, respectively. Liver stiffness was not affected by hepatic steatosis, necroinflammation, or body mass index. Discordance of at least two stages between transient elastography and histology was observed in 33 (13.4%) patients. By multivariate analysis, liver biopsy length less than 20 mm and F0‐2 disease were associated with discordance. Conclusion: Transient elastography is accurate in most NAFLD patients. Unsatisfactory liver biopsy specimens rather than transient elastography technique account for most cases of discordance. With high negative predictive value and modest positive predictive value, transient elastography is useful as a screening test to exclude advanced fibrosis. Liver biopsy may be considered in NAFLD patients with liver stiffness of at least 7.9 kPa. (HEPATOLOGY 2010;51:454–462.)

Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years

Background Patients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive. Objective To investigate disease progression in patients with different degrees of non-alcoholic fatty liver disease (NAFLD) activity. Design Prospective longitudinal hospital-based cohort study. Patients Fifty-two patients (age 44±9 years) with biopsy-proven NAFLD had liver biopsies repeated at month 36. Results Among 13 patients with simple steatosis at baseline, 2 (15%) had a normal liver at month 36, 3 (23%) continued to have simple steatosis, 5 (39%) developed borderline NASH and 3 (23%) developed NASH. Among 22 patients with borderline NASH at baseline, 4 (18%) had simple steatosis and 13 (59%) had borderline NASH at month 36, while 5 (23%) developed NASH. Among 17 patients with NASH at baseline, 10 (59%) continued to have NASH and 6 (35%) had borderline NASH at month 36. Only 1 (6%) patient regressed to simple steatosis. Overall, 14 (27%) patients had fibrosis progression, 25 (48%) had static disease, and 13 (25%) had fibrosis regression. Reduction in body mass index and waist circumference was independently associated with non-progressive disease activity and fibrosis. The baseline serum levels and month 36 changes in adiponectin, tumour necrosis factor α, interleukin 6 and leptin were not associated with disease progression. Serum cytokeratin-18 fragment level reflected disease activity and its change correlated with the change in NAFLD activity score (R=0.51, p<0.001). Conclusions Patients with simple steatosis may still develop NASH and fibrosis progression. Weight reduction is associated with non-progressive disease. All patients with NAFLD should undergo periodic assessment and lifestyle modification.

High Viral Load and Hepatitis B Virus Subgenotype Ce Are Associated With Increased Risk of Hepatocellular Carcinoma

PURPOSE We aimed to investigate the impact of hepatitis B virus (HBV) DNA and HBV genotypes/subgenotypes on the risk of hepatocellular carcinoma (HCC). PATIENTS AND METHODS A prospective cohort of patients infected with chronic HBV in a surveillance program for HCC since 1997 was studied. Ultrasound and alpha-fetoprotein evaluation were regularly performed to detect HCC. Risk factors for HCC and the relationship between HBV DNA and HBV genotypes were determined. RESULTS Among 1,006 patients with a median follow-up of 7.7 years, 86 patients (8.5%) developed HCC. With reference to the low HBV DNA stratum (log HBV DNA </= 4.5 copies/mL), the hazard ratio for HCC of the intermediate HBV DNA stratum (log HBV DNA > 4.5 to 6.5 copies/mL) was 1.62 (95% CI, 1.05 to 2.48; P = .027) and that of the high HBV DNA stratum (log HBV DNA > 6.5 copies/mL) was 2.73 (95% CI, 1.76 to 4.25; P < .001). Among patients with genotyping results, 330 patients had HBV genotype B and 439 patients had HBV genotype C (94 subgenotype Ce and 345 subgenotype Cs). With reference to HBV genotype B, HBV subgenotype Ce has the highest risk of HCC (hazard ratio = 2.75; 95% CI, 1.66 to 4.56; P < .0001) and HBV subgenotype Cs has intermediate risk (hazard ratio = 1.70; 95% CI, 1.09 to 2.64; P = .020). On multivariate analysis, HBV DNA, HBV genotypes, liver cirrhosis, male sex, older age, and lower serum albumin were independent risk factors of HCC. CONCLUSION High HBV DNA level and HBV genotype C, particularly subgenotype Ce, increased the risk of HCC in chronic hepatitis B.

Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers

PURPOSE Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers. PATIENTS AND METHODS We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients. RESULTS During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively. CONCLUSION A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted.

Causes of Mortality in Patients With Peptic Ulcer Bleeding: A Prospective Cohort Study of 10,428 Cases

OBJECTIVES:Despite advances in endoscopic and pharmacological treatment for peptic ulcer bleeding (PUB), mortality remains at 5–10% worldwide. Our aim was to investigate the causes of death in a prospective cohort of PUB in a tertiary referral center.METHODS:Between 1993 and 2005, all patients with upper gastrointestinal bleeding (UGIB) admitted to the Prince of Wales Hospital were prospectively registered. Demographic data, characteristics of ulcer, and pharmacological, endoscopic, and surgical therapy, were documented. Mortality cases were classified as (A) bleeding-related death (A1: uncontrolled bleeding, A2: within 48 h after endoscopy, A3: during surgery for uncontrolled bleeding, A4: surgical complications or within 1 month after surgery, and A5: endoscopic related mortality) or (B) non-bleeding-related death (B1: cardiac causes, B2: pulmonary causes, B3: cerebrovascular disease, B4: multiorgan failure, and B5: terminal malignancy).RESULTS:In all, 18,508 cases of UGIB were enrolled; among them, 10,428 cases from 9,375 patients were confirmed to have PUB, and 577 (6.2%) patients died. There were significantly more patients who died of non-ulcer bleeding causes (79.7%) than bleeding causes (18.4%). The mean (s.d.) age of those who died of bleeding-related causes was higher (75.4 (12.6) years) than that of those who died of non-bleeding causes (71.7 (13.1) years) (P=0.010). Most bleeding-related deaths occurred when immediate control of bleeding failed (29.2%) or when patients died within 48 h after endoscopic therapy (25.5%). Among those who died of non-bleeding-related causes, multiorgan failure (23.9%), pulmonary conditions (23.5%), and terminal malignancy (33.7%) were most common.CONCLUSIONS:The majority of PUB patients died of non-bleeding-related causes. Optimization of management should aim at reducing the risk of multiorgan failure and cardiopulmonary death instead of focusing merely on successful hemostasis.

Systematic Review of the Epidemiology of Complicated Peptic Ulcer Disease: Incidence, Recurrence, Risk Factors and Mortality

Background/Aims: The incidence of uncomplicated peptic ulcer has decreased in recent years. It is unclear what the impact of this has been on the epidemiology of peptic ulcer complications. This systematic review aimed to determine the incidence, recurrence and mortality of complicated peptic ulcer and the risk factors associated with these events. Methods: Systematic PubMed searches. Results: Overall, 93 studies were identified. Annual incidence estimates of peptic ulcer hemorrhage and perforation were 19.4–57.0 and 3.8–14 per 100,000 individuals, respectively. The average 7-day recurrence of hemorrhage was 13.9% (95% CI: 8.4–19.4), and the average long-term recurrence of perforation was 12.2% (95% CI: 2.5–21.9). Risk factors for peptic ulcer complications and their recurrence included nonsteroidal anti-inflammatory drug and/or acetylsalicylic acid use, Helicobacter pylori infection and ulcer size ≧1 cm. Proton pump inhibitor use reduced the risk of peptic ulcer hemorrhage. Average 30-day mortality was 8.6% (95% CI: 5.8–11.4) after hemorrhage and 23.5% (95% CI: 15.5–31.0) after perforation. Older age, comorbidity, shock and delayed treatment were associated with increased mortality. Conclusions: Complicated peptic ulcer remains a substantial healthcare problem which places patients at a high risk of recurrent complications and death.

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±22 weeks, 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.

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.

Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection.

OBJECTIVES:We aimed to study the relationship between the hepatitis B virus (HBV) genotypes, core promoter/precore stop codon mutations, and histological liver damage among hepatitis B e antigen (HBeAg)-negative patients.METHODS:Liver biopsy specimens of 55 HBeAg-negative chronic HBV-infected patients were studied. A histological activity index was scored for degree of necroinflammation (HAI-NI) and fibrosis (HAI-F) as described by Knodell et al. HBV DNA was determined by a cross-linking assay and polymerase chain reaction (PCR) at the core promoter/precore region and the S region. PCR-positive samples were directly sequenced for core promoter and precore mutations and examined by restriction fragment length polymorphism for genotyping.RESULTS:Forty-one males and 14 females at a median age of 43 were studied. HBV DNA was detectable in 32 (58%) and 37 (67%) patients by the cross-linking assay and PCR, respectively, at the time of liver biopsy. The median (range) HAI-NI and HAI-F scores were 5 (1–10) and 2 (0–4), respectively. HBV DNA detectable by either the cross-linking assay or PCR was associated with a higher HAI-NI score. Eleven and 31 patients had genotypes B and C HBV, respectively. Genotype C HBV was associated with higher HAI-NI than genotype B HBV. Core promoter mutations and precore stop codon mutation were detected in 74% and 40% patients, respectively, but they were not associated with higher HAI-NI or HAI-F scores.CONCLUSIONS:Detectable HBV DNA and genotype C HBV, but not core promoter or precore stop codon mutations, are associated with more severe liver damage in HBeAg-negative patients.