Quantitative HBeAg is a strong predictor of HBeAg loss among patients receiving pegylated interferon.

BACKGROUND: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy. AIM: To evaluate the use of serum biomarkers to predict HBeAg loss. METHODS: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated. RESULTS: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm. CONCLUSIONS: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.

Comparing serial and current liver stiffness measurements to predict decompensation in compensated advanced chronic liver disease patients.

INTRODUCTION: The utility of serial liver stiffness measurements (LSM) to predict decompensation in compensated advanced chronic liver disease (cACLD) patients remains unclear. We aimed to validate whether comparing serial LSM is superior to using the current LSM to predict liver-related events (LRE) in cACLD patients. METHODS: In this retrospective analysis of an international registry, cACLD patients with serial LSM were followed up until index LRE. We compared the performance of both the dynamic LSM changes and the current LSM (LSMc ) in predicting LRE using Cox-regression analysis, considering time zero of follow-up as the date of LSMc. RESULT: 480 cACLD patients with serial LSM were included from 5 countries. The commonest etiology of cACLD was viral (53%) and MASLD (34%). Over a median follow-up of 68 (45-92) months, 32% experienced LSM decrease to levels below 10kPa (resolved-cACLD) and 5.8% experienced LRE. Resolved-cACLD were more likely to be non-diabetic and had better liver function. While a higher value of the current LSM (LSMc) was associated with higher LREs, LSM changes over time (LSM slope) were not associated with LRE. In multivariable Cox regression, both prior LSM and LSM slope did not add predictive value to LSMc. CONCLUSION: Once the current LSM is known, previous LSM values do not add to the prediction of LREs in cACLD patients.

Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT.

BACKGROUND & AIMS: The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA. METHODS: We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 µg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT). RESULTS: A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy). CONCLUSIONS: ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Immunoglobulin G in non-alcoholic steatohepatitis predicts clinical outcome: A prospective multi-centre cohort study.

BACKGROUND: Autoimmune markers including plasma cells (PC), anti-smooth-muscle antibody (ASMA), anti-nuclear antibody (ANA), and raised immunoglobulin G (IgG) are commonly observed in non-alcoholic steatohepatitis (NASH), however their clinical significance is unknown. AIM: To determine if autoimmune markers in NASH patients are independently associated with poorer clinical outcomes. METHODS: Consecutive patients with biopsy proven NASH from Christchurch Hospital, New Zealand and Singapore General Hospital (SGH) were included between 2005 to 2016 in a prospective multi-centre cohort study. Patients with other causes of chronic liver disease were excluded. IgG > 14 g/L or globulin fraction > 50%, ANA ≥ 1:40, SMA ≥ 1:40 were considered positive. Multivariate analysis was performed to assess which markers were independently associated with mortality and hepatic decompensation. RESULTS: Total 261 patients were included of which 201 were from SGH. The median age was 53 and 51.9% were male. Advanced fibrosis was present in 31.4% at diagnosis. PC, ASMA, ANA and raised IgG were observed in 13.1%, 4.9%, 27.8% and 30.1% of patients respectively. After multivariate analysis, elevated IgG [Hazard Ratio (HR) 6.79, 95%CI: 2.93-17.15] and fibrosis stage (HR 1.37, 95%CI: 1.03-1.87) were found to be independently associated with increased risk of liver decompensation. Age (HR 1.06, 95%CI: 1.02-1.10) and elevated IgG (HR 3.79, 95%CI: 1.90-7.68) were independent factors associated with higher mortality risk. CONCLUSION: Elevated IgG, rather than ANA, ASMA or plasma cells, is independently associated with increased risk of hepatic decompensation and mortality in NASH. It could hence be important for prognostication.

Trends in Incidence of Autoimmune Liver Diseases and Increasing Incidence of Autoimmune Hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are autoimmune liver diseases of unknown etiology. We studied trends in incidences of AIH, PBC, and PSC in a population-based prospective study Canterbury, New Zealand. METHODS: We collected data on patients with AIH (n = 99), PBC (n = 26), or PSC (n = 47) from public hospitals and private practices in Canterbury from 2008 through 2016. Diagnoses were made based on international standardized criteria. We calculated incidence rates for the time periods of 2008-2010, 2011-2013, and 2014-2016 and compared them using 2-tailed mid-P exact tests. RESULTS: Overall incidence rates were 1.93 per 100,000 for AIH (95% CI, 1.58-2.34), 0.51 per 100,000 for PBC (95% CI, 0.33-0.73), and 0.92 per 100,000 for PSC (95% CI, 0.68-1.21). The incidence of AIH was significantly higher during the period of 2014-2016 (2.39 per 100,000; 95% CI, 1.76-3.23) than during the period of 2008-2010 (1.37 per 100,000; 95% CI, 0.91- 2.06) (P < .05). Incidences of PBC and PSC did not change significantly. In 2016, prevalence values were 27.4 per 100,000 for AIH (95% CI, 23.58-32.0), 9.33 per 100,000 for PBC (95% CI, 7.13-12.05), and 13.17 per 100,000 for PSC (95% CI, 10.56-16.42). CONCLUSIONS: In a population-based prospective study, we found that the incidence of AIH was significantly higher in the 2014-2016 period than the 2008-2010 period; incidences of PBC and PSC were unchanged over the same period. Further studies are needed to determine the reasons for changes in incidence of autoimmune liver diseases.

Comparative biomarkers for HBsAg loss with antiviral therapy shows dominant influence of quantitative HBsAg (qHBsAg).

BACKGROUND: Biomarkers such as quantitative HBsAg (qHBsAg), quantitative hepatitis B virus (HBV) core-related antigen (qHBcrAg) and HBV RNA may be useful in predicting HBsAg loss in patients with chronic hepatitis B (CHB) undergoing antiviral therapy. AIM(S): Our study evaluated qHBsAg, HBV RNA and qHBcrAg as a posthoc analysis of a randomized clinical trial of peginterferon±NA to determine their utility in predicting HBsAg loss. METHODS: CHB patients who completed therapy with 48weeks peginterferon alpha2b ± nucleoside analogue therapy (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBsAg loss. The predictive ability of qHBsAg, qHBcrAg, HBV RNA and other variables were investigated by univariate and multivariate logistic models for HBeAg-negative patients by odds ratios, area under the curve (AUC), sensitivity, specificity, and positive and negative likelihood ratios (LR). RESULTS: HBsAg loss occurred in 15/114(13%) HBeAg-negative CHB patients who completed 48 weeks of peginterferon. At baseline, qHBsAg was superior to HBcrAg and HBV RNA with AUC 0.916, 0.649 and 0.542, respectively. Using multivariate analysis, the model comprising treatmentarm, age, gender, baseline qHBsAg, HBcrAg and HBV RNA, weeks 4 & 8 qHBsAg had the highest AUC(0.98), but the univariate model with week 8 qHBsAg <70 IU/mL had AUC 0.96. Hence, the contributions of variables other than qHBsAg were marginal. HBV RNA and qHBcrAg were weak predictors of HBsAg loss. Kinetics of the novel markers showed only qHBsAg had a good relationship with HBsAg loss while HBV RNA had a marginal relationship and HBcrAg did not change at all, and none had a good relationship with viral rebound. CONCLUSIONS: On-treatment biomarker predictors were better than baseline ones, and the best predictor of HBsAg loss at 72 weeks was week 8 qHBsAg <70 IU/mL.

Use of over-the-scope-clip (OTSC) improves outcomes of high-risk adverse outcome (HR-AO) non-variceal upper gastrointestinal bleeding (NVUGIB).

BACKGROUND AND STUDY AIMS: Endoscopic treatment of non-variceal upper gastrointestinal bleeding (NVUGIB) with high-risk adverse outcome (HR-AO) features has a high risk of failure. We studied the safety and efficacy of over-the-scope clips (OTSC) to treat these lesions. PATIENTS AND METHODS: We included patients who were treated using OTSC for NVUGIB from January 2015 to October 2017. We studied rebleeding and mortality rates and used the Rockall data and our institution's prior data for comparison. We used descriptive and chi-square statistics. RESULTS: We studied 18 patients with 19 bleeding lesions: 9 (47 %) duodenal ulcers, 4 (21 %) Dieulafoy's lesion, 3 (16 %) gastric ulcer, and 3 (16 %) bleeding after gastric biopsy, gastric polypectomy and endoscopic ultrasound-guided fine-needle aspiration of peri-gastric mass. We applied OTSC as the first-line treatment in 10 (53 %) and as the second-line treatment in 9 (47 %) bleeding lesions. Continued bleeding after OTSC occurred in six patients, but we treated it successfully and achieved complete hemostasis in all patients. We found OTSC use significantly decreased (0 % vs. 53 %, P  < 0.01) and reduced (0 % vs. 24 %, P  = 0.08) the rebleeding rate in our high-risk (RS ≥ 8) and intermediate-risk (RS = 4 - 7) Rockall score patients as compared to the rates reported by the Rockall study, respectively. When compared to our institution's prior study, we found a decrease in the rebleeding rate with OTSC (0 % vs. 21 %, P  = 0.06) in our intermediate-to-high risk Rockall score patients (RS ≥ 4). There was no difference in mortality rates as compared to both control studies. CONCLUSION: Use of OTSC is safe, efficacious and appears superior to standard treatment for HR-AO NVUGIB. OTSC should be considered as first-line treatment for HR-AO bleeding.

Colorectal cancer screening.

Colorectal cancer, which is the leading cancer in Singapore, can be prevented by increased use of screening and polypectomy. A range of screening strategies such as stool-based tests, flexible sigmoidoscopy, colonoscopy and computed tomography colonography are available, each with different strengths and limitations. Primary care physicians should discuss appropriate screening modalities with their patients, tailored to their individual needs. Physicians, patients and the government should work in partnership to improve uptake of colorectal cancer screening to reduce the morbidity and mortality from colorectal cancer.

Managing non-alcoholic fatty liver disease.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly with the obesity and diabetes mellitus epidemics. It is rapidly becoming the most common cause of liver disease worldwide. NAFLD can progress to serious complications such as cirrhosis, hepatocellular carcinoma and death. Therefore, it is important to recognise this condition so that early intervention can be implemented. Lifestyle modifications and strict control of metabolic risk factors are the mainstay of treatment. As disease progression is slow in the majority of NAFLD patients, most can be managed well by primary care physicians. NAFLD patients with advanced liver fibrosis should be referred to specialist care for further assessment.

Difference in clinical presentation, immunology profile and treatment response of type 1 autoimmune hepatitis between United Kingdom and Singapore patients.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease of unknown etiology. Increasing incidence of AIH in Asian patients has been reported. However, the phenotypic difference of Asian patients in Europe and Asia has still not been explored. AIM: To evaluate the clinical presentation, biochemical and immunological profiles, treatment response and survival outcome of type 1 AIH from two tertiary liver transplant centres (United Kingdom and Singapore). METHOD: Patients who fulfilled the simplified diagnostic scoring criteria of AIH were included in the study. Patients with overlap syndrome were excluded. RESULTS: Totals of 40 Asian patients and 159 Caucasian patients from the University Hospital of Birmingham National Health Service Foundation Trust, UK, were compared with 57 Asian patients from Singapore General Hospital, Singapore. Asian patients from Singapore present significantly much later (median 55 vs. 32 years, p < 0.001), had higher MELD (p < 0.001) with lower albumin (p < 0.001) and higher bilirubin (p < 0.001) and lower ASMA positivity (p < 0.001) at diagnosis compared to UK Asian. Jaundice at presentation was much higher in Singapore Asian patients compared to UK Asian (53 vs. 30 %) but cirrhosis at diagnosis was more common in UK patients. Associated autoimmune conditions were less commonly seen in Singapore Asians. Comparing between UK cohorts, Asian patients present at younger age and have higher IgG level compared to Caucasian. Overall, 5-year transplant-free survival in all three cohorts was similar (p = 0.846). CONCLUSION: We demonstrate that AIH patients from Singapore present at older age with jaundice and have a low positivity of SMA. Despite these differences, transplant-free survival is similar in the two groups.

Clinical applications, limitations and future role of transient elastography in the management of liver disease.

Transient elastography (TE) is a reliable tool for the non-invasive assessment of liver fibrosis in routine clinical practice. TE is currently approved for use in Europe, Asia and the United States. The widespread adoption of this technology is certain to increase the use of TE worldwide. Although TE has been well validated in chronic viral hepatitis, its clinical role in other liver diseases remains less clear. The advent of new treatment for chronic hepatitis C and emerging prevalence of non-alcoholic steatohepatitis raises new questions on the role of TE in current clinical practice. This review aims to examine the clinical applications, limitations and future role of TE in current clinical practice in light of the changing epidemiology of liver diseases and new clinical management paradigms. In current clinical practice, TE is the most accurate non-invasive method for diagnosis of liver cirrhosis. TE is useful to rule out fibrosis and cirrhosis but does not have sufficient accuracy to discern between various stages of fibrosis. The clinical role of TE has evolved from cross-sectional point-in-time assessment of fibrosis and cirrhosis to the more relevant role of prediction of vital clinical end-points. This provides clinicians with the ability to modify treatment strategies based on the information provided by TE. TE has evolved over the past decade to become an essential tool to assist the clinician in the management of chronic liver disease.

Predictors of poor outcome in patients w ith autoimmune hepatitis: a population-based study.

UNLABELLED: Autoimmune hepatitis (AIH) can lead to cirrhosis, hepatic failure, and death. We aimed to identify predictors of advanced liver fibrosis at presentation, predictors of incomplete response to initial immunosuppression, and predictors of poor liver-related outcomes in the population-based AIH cohort from Canterbury, New Zealand. Cases diagnosed after 1980 that fulfilled standard diagnostic criteria were included. Cases were censored at death or liver transplantation and had a median follow-up of 9 years. Analyses were performed with Cox proportional hazards regression and logistic binary regression. The times to event outcomes were summarized using Kaplan-Meier curves. A total of 133 AIH patients were included. Predictors for advanced liver fibrosis at diagnosis were age at presentation of ≤20 years or >60 years (P = 0.02), serum albumin <36 g/L (P < 0.01), platelet <150 U/L (P < 0.01), and International Normalized Ratio (INR) >1.2 (P < 0.01). The only independent predictor for incomplete normalization of alanine aminotransferase (ALT) at 6 months was age at presentation ≤20 years. Independent predictors of poor liver-related outcomes were incomplete normalization of ALT at 6 months (P < 0.01), serum albumin <36 g/L (P < 0.01), and age at presentation of ≤20 years or >60 years (P = 0.01). Kaplan-Meier estimates showed that 10-year adverse liver event-free survival was 80% for age at presentation ≤20 years and >60 years, and 93% and 100% for age at presentation between 21-40 years and 41-60 years, respectively. CONCLUSION: Incomplete normalization of ALT at 6 months, low serum albumin concentration at diagnosis, and age at presentation of ≤20 years or >60 years were significant independent predictors of liver-related death or requirement for liver transplantation. Histological cirrhosis at diagnosis was not associated with poor prognosis and did not influence the response to initial immunosuppressive treatment. (HEPATOLOGY 2013;57:2399-2406).

Mortality and the risk of malignancy in autoimmune liver diseases: a population-based study in Canterbury, New Zealand.

UNLABELLED: Population-based quantitative data on the mortality and cancer incidence of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) are scarce. Our aim was to systematically investigate the survival and risk of malignancy on population-based cohorts of AIH, PBC, and PSC in Canterbury, New Zealand. Multiple case-finding methods were employed, including searches of all public and private, adult and pediatric outpatient clinics, hospital notes, laboratory, radiology, and pathology reports. Cases that fulfilled standardized diagnostic criteria were included. Kaplan-Meier survival estimates, standardized mortality ratios (SMR), and standard incidence ratios (SIR) for malignancy were calculated. A total of 130 AIH, 70 PBC, and 81 PSC patients were included contributing to 1,156, 625, and 613 person-years at risk, respectively. For AIH, PBC, and PSC cohorts, SMRs for all-cause mortality were 2.1 (95% confidence interval [CI] 1.4-3.1), 2.7 (95% CI 1.7-4.0), and 4.1 (95% CI 2.6-6.3), SMRs for hepatobiliary mortality were 42.3 (95% CI 20.3-77.9), 71.2 (95% CI 30.7-140.3), and 116.9 (95% CI 66.8-189.8), SIRs for all cancers were 3.0 (95% CI 2.0-4.3), 1.6 (95% CI 0.8-2.9), and 5.2 (95% CI 3.3-7.8), and SIRs for extrahepatic malignancy were 2.7 (95% CI 1.8-3.9), 1.6 (95% CI 0.8-2.9), and 3.0 (95% CI 1.6-5.1), respectively. CONCLUSION: This is the first population-based study to examine and compare the survival and cancer incidence in AIH, PBC, and PSC in the same population. The mortality for all three cohorts was significantly increased due to liver-related death, demonstrating the inadequacy of current management strategies. The risk of hepatic and extrahepatic malignancy was significantly increased in AIH and PSC patients.

Low incidence and prevalence of primary biliary cirrhosis in Canterbury, New Zealand: a population-based study.

PURPOSE: Epidemiological data on primary biliary cirrhosis (PBC) in the Southern Hemisphere is scarce. Our aim was to perform a population-based epidemiological study of PBC in Canterbury, New Zealand. METHODS: Multiple case-finding methods were employed. All public and private, adult and pediatric outpatient clinics, hospital discharge summaries, and laboratory and pathology reports were searched to identify all cases in the region. Cases were included if at least two of the following criteria were fulfilled: (1) positive anti-mitochondrial antibodies, (2) elevated alkaline phosphatase for greater than 6 months, and (3) compatible liver histology. RESULTS: A total of 71 cases of PBC were included. The incidence in 2008 was 0.8 (95% confidence interval (CI) 0.1-1.6) per 100,000. The point prevalence on December 31, 2008 was 9.9 (95% CI 7.1-12.7) per 100,000. Male to female ratio was 1:11. At presentation, 45% were asymptomatic. Age at diagnosis peaked at the seventh decade with mean age at diagnosis of 61 (95% CI 58-64). CONCLUSIONS: This is the first population-based epidemiological study of PBC conducted in New Zealand and only the second in the Southern Hemisphere. The incidence and prevalence are lower than the Northern Hemisphere, even though the majority of our population has shared genetic background with some of these countries. Our study has provided further support to the hypothesis that there may be a protective effect or lack of a risk factor for PBC in New Zealand.

Inflammatory bowel disease is associated with poor outcomes of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Little is known about the exact etiology of primary sclerosing cholangitis (PSC); epidemiologic data are scarce. We performed a population-based epidemiologic study of PSC in Canterbury, New Zealand. METHODS: By using multiple case-finding methods, we searched public and private adult and pediatric outpatient clinics, hospital discharge summaries, and radiology and pathology reports to identify all cases of PSC in the region. Cases were included if PSC was identified by endoscopic retrograde cholangiography, magnetic resonance cholangiography, or liver biopsy analysis (n = 79). RESULTS: The incidence of PSC in 2008 was 1.6 per 100,000 persons (95% confidence interval [CI], 0.5-2.7). The point prevalence on December 31, 2008, was 11.7 per 100,000 persons (95% CI, 8.7-14.8). The mean and median ages at diagnosis were 50 years (95% CI, 46-53 years) and 49 years (range, 17-80 years), respectively. Patients who had inflammatory bowel disease (IBD) presented with PSC earlier than those without IBD (P = .003), were more likely to develop serious malignant complications (P = .017), and were more likely to require liver transplantation or die (P = .03). CONCLUSIONS: In a population-based epidemiology study of PSC in Canterbury, New Zealand, we observed large differences between PSC patients with or without concurrent IBD in age at diagnosis, development of cancer, mortality, and requirement for liver transplantation. IBD therefore affects outcomes of patients with PSC, an important observation that requires further study.