Idiopathic multitudinous fundic gland polyposis: A new disease and a management dilemma.

Two patients with idiopathic multitudinous fundic gland polyposis, a hitherto undescribed condition, were reported. They presented incidentally with a multitude of fundic gland polyps, 52 and 147, without a family history of polyposis, and these polyps were not attributable to the chronic use of proton pump inhibitors. All polyps were removed by hot-biopsy polypectomy, and each was individually subjected to pathological examination, which showed no evidence of dysplasia. When confronted with gastric polyps of clinically undetermined origin, endoscopists would, to exclude dysplasia, usually resect all if they are few and sample some and survey the others periodically if they are numerous. The condition reported presents a management dilemma: Because the number of the polyps is such that they are manageable by total polypectomy, should this be carried out, despite the labor intensiveness involved, to exclude dysplasia, and are the polyps a variant of syndromic polyposis and therefore carry a malignant potential and inform the need for periodic surveillance and to investigate the patient's kindred? The frequency of this condition and whether it is truly not associated with dysplasia require further studies.

Impact of metabolic risk factors on the severity and outcome of patients with alcohol-associated acute-on-chronic liver failure.

BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.

APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.

APASL clinical practice recommendation: how to treat HCV-infected patients with renal impairment?

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.

APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing.

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.

APASL consensus statements and recommendation on treatment of hepatitis C.

The Asian-Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL consensus statements and recommendation on management of hepatitis C" in March, 2015, in order to revise "APASL consensus statements and management algorithms for hepatitis C virus infection (Hepatol Int 6:409-435, 2012)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations on treatment of hepatitis C are presented in this review.

Features of hepatitis C virus infection, current therapies and ongoing clinical trials in ten Asian Pacific countries.

Estimated hepatitis C virus (HCV) infection rates in the general populations were 1.3, 0.9, 0.4-1.0, 14.7, 0.1-0.3, 0.9-1.9, 1.0-2.0, 5, 4.4-8.6 and 0.5-1.3 % in Australia, Bangladesh, Mainland China, Egypt, Hong Kong, India, Japan, Pakistan, Taiwan and Turkey, respectively. The main HCV genotypes (Gs) are G1, G3, G1b, G4, G1b, G3, G1b, G3, G1b and G2, and G1 in Australia, Bangladesh, Mainland China, Egypt, Hong Kong, India, Japan, Pakistan, Taiwan and Turkey, respectively. Of IL28B genotypes, favorable alleles are ~50 % in Australia and Turkey, but 60-70 % in most of the other Asian countries. Peginterferon plus ribavirin is available in all ten Asian Pasific countries. In addition, HCV NS3/4A protease inhibitors with peginterferon plus ribavirin are currently available in several countries. Clinical trials of interferon-free regimens for HCV are ongoing in most of the ten Asian Pacific countries.

Preemptive adefovir versus lamivudine for prevention of hepatitis B reactivation in chronic hepatitis B patients undergoing chemotherapy.

BACKGROUND: This proof-of-concept study compared lamivudine (LAM) with a newer antiviral agent, adefovir dipivoxil (ADF), in preventing hepatitis B virus (HBV) reactivation in chronic HBV patients undergoing chemotherapy. METHODS: Hepatitis B surface antigen (HBsAg) positive patients intended to undergo chemotherapy were randomized to receive either LAM 100 mg daily or ADF 10 mg daily. Anti-viral therapy was started 1 week prior to chemotherapy and until 6 months after completing chemotherapy. The primary outcome was HBV reactivation rate. All patients with viral breakthrough were screened for resistance mutations by direct sequencing. RESULTS: Seventy treatment-naïve patients were consecutively randomized 1:1 to LAM or ADF. The median baseline HBV DNA levels were similar (LAM 3.36 vs. ADF 3.17 log10 copies/mL, p = 0.860). The median duration was 8.3 months on LAM and 10.6 months on ADF (p = 0.220). HBV reactivation was observed in 13/35 (37.1%) on LAM compared with 10/35 (28.6%) on ADF (p = 0.611). The median time to HBV reactivation was 4.6 and 8.1 months, on LAM and ADF respectively. Among these 13 patients, 8/13 (61.5%) on LAM had developed drug resistance mutations but none on ADF had developed drug resistance mutations to ADF (p = 0.003). Both drugs were well tolerated and no severe drug-related toxicities were reported. CONCLUSION: In this randomized clinical study, adefovir and lamivudine demonstrated similar efficacy in preventing hepatitis B reactivation in HBsAg-positive patients undergoing chemotherapy. In patients whose hepatitis B reactivated, adefovir was associated with a lower resistance profile.

Early Viral Kinetics with Telbivudine, Tenofovir or Combination of Both in Immunotolerant Patients with Hepatitis B e Antigen-Positive Chronic Hepatitis B.

INTRODUCTION: Viral kinetics has proved useful in understanding antiviral potency, determining antiviral profiles and optimizing treatment strategy. METHODS: This was a randomized, open-label study comparing the viral kinetics in 46 hepatitis B e antigen-positive patients during 12-week treatment with telbivudine monotherapy, tenofovir monotherapy or the combination of telbivudine plus tenofovir. A standard biphasic mathematical model was used to compare hepatitis B virus (HBV) DNA decay parameters. RESULTS: Forty-six patients received telbivudine (n = 16), tenofovir (n = 14) or telbivudine plus tenofovir (n = 16). From baseline to Week 12, the mean (SD) reduction in HBV DNA levels was not significantly different between treatment groups: -3.9 (0.9) log10 copies/mL in telbivudine group, -4.2 (0.7) log10 copies/mL in tenofovir group, and -4.4 (1.0) log10 copies/mL in combination group. No significant difference was observed among the three groups for viral clearance rate per day (0.97, 1.02, and 0.88, respectively) or for infected cell loss rate per day (0.04, 0.05, and 0.05, respectively). Antiviral efficiency in blocking viral production was similar in the monotherapy groups (median; 99.7% in telbivudine group and 99.4% in tenofovir group), but was slightly better and more homogeneous in the combination treatment group than in the monotherapy groups: mean (SD), 99.1% (0.8%) and 98.8% (1.6%), respectively (Wald-Wolfowitz test; P = 0.038). All treatments were well tolerated and no serious adverse event was reported during the study. Of the 46 patients in the safety population, 23 experienced adverse events. Most of the adverse events were not suspected to be related to the study drug by the investigators. CONCLUSION: Monotherapy with telbivudine or tenofovir showed similar antiviral effectiveness in HBV DNA reduction and viral kinetics of HBV DNA decay. Efficiency in blocking viral production was slightly improved in the combination treatment group compared to the monotherapy groups.

Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma.

UNLABELLED: The role of CD4(+) cytotoxic T cells (CTLs) in hepatocellular carcinoma (HCC) remains obscure. This study characterized CD4(+) CTLs in HCC patients and further elucidated the associations between CD4(+) CTLs and HCC disease progression. In all, 547 HCC patients, 44 chronic hepatitis B (CHB) patients, 86 liver cirrhosis (LC) patients, and 88 healthy individuals were enrolled in the study. CD4(+) CTLs were defined by flow cytometry, immunohistochemistry, and lytic granule exocytosis assays. A multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Circulating and liver-infiltrating CD4(+) CTLs were found to be significantly increased in HCC patients during early stage disease, but decreased in progressive stages of HCC. This loss of CD4(+) CTLs was significantly correlated with high mortality rates and reduced survival time of HCC patients. In addition, the proliferation, degranulation, and production of granzyme A, granzyme B, and perforin of CD4(+) CTLs were inhibited by the increased forkhead/winged helix transcription factor (FoxP3(+) ) regulatory T cells in these HCC patients. Further analysis showed that both circulating and tumor-infiltrating CD4(+) CTLs were independent predictors of disease-free survival and overall survival after the resection of the HCC. CONCLUSION: The progressive deficit in CD4(+) CTLs induced by increased FoxP3(+) regulatory T cells was correlated with poor survival and high recurrence rates in HCC patients. These data suggest that CD4(+) CTLs may represent both a potential prognostic marker and a therapeutic target for the treatment of HCC.

Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients.

Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study.

BACKGROUND/AIMS: Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. METHODS: In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. RESULTS: Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. CONCLUSIONS: A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B.

Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers.

UNLABELLED: Although threshold levels for hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) titers have recently been proposed to guide therapy for chronic hepatitis B (CHB), their relationship to circulating hepatitis B virus (HBV) DNA and intrahepatic HBV replicative intermediates, and the significance of emerging viral variants, remains unclear. We therefore tested the hypothesis that HBsAg and HBeAg titers may vary independently of viral replication in vivo. In all, 149 treatment-naïve CHB patients were recruited (HBeAg-positive, n = 71; HBeAg-negative, n = 78). Quantification of HBeAg and HBsAg was performed by enzyme immunoassay. Virological characterization included serum HBV DNA load, HBV genotype, basal core promoter (BCP)/precore (PC) sequence, and, in a subset (n = 44), measurement of intrahepatic covalently closed circular DNA (cccDNA) and total HBV DNA, as well as quantitative immunohistochemical (IHC) staining for HBsAg. In HBeAg-positive CHB, HBsAg was positively correlated with serum HBV DNA and intrahepatic cccDNA and total HBV DNA (r = 0.69, 0.71, 0.76, P < 0.01). HBeAg correlated with serum HBV DNA (r = 0.60, P < 0.0001), although emerging BCP/PC variants reduced HBeAg titer independent of viral replication. In HBeAg-negative CHB, HBsAg correlated poorly with serum HBV DNA (r = 0.28, P = 0.01) and did not correlate with intrahepatic cccDNA nor total HBV DNA. Quantitative IHC for hepatocyte HBsAg confirmed a relationship with viral replication only in HBeAg-positive patients. CONCLUSION: The correlation between quantitative HBsAg titer and serum and intrahepatic markers of HBV replication differs between patients with HBeAg-positive and HBeAg-negative CHB. HBeAg titers may fall independent of viral replication as HBeAg-defective variants emerge prior to HBeAg seroconversion. These findings provide new insights into viral pathogenesis and have practical implications for the use of quantitative serology as a clinical biomarker.