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Objective: This study was designed to prospectively evaluate the antiviral responses and evolution of resistance mutations during adefovir (ADV) plus lamivudine (LMV) therapy in patients with entecavir (ETV)-resistant hepatitis B virus (HBV) infection. Methods: Twenty chronic hepatitis B (CHB) patients who had been receiving ETV for more than 6 months and developed virologic breakthrough due to ETV resistance were consecutively enrolled. Results: Patients received ADV plus LMV therapy for 12 months. The baseline mean serum HBV DNA level was 5.59 ± 1.28 log10 IU/ml. The rtT184L/I/A/F (50%), rtS202G (25%) and mixed ETV-resistant mutations (25%) were detected at enrollment. The mean reduction in serum HBV DNA levels from baseline to 12 months was -2.3 ± 1.06 log10 IU/ml (p < 0.001). Seventeen patients were followed up for the full 12 months, and complete virologic response (HBV DNA <20 IU/ml) was observed in 4 patients (23.5%). Among the remaining 13 patients who still had detectable HBV DNA, 7 patients showed disappearance of ETV-resistant mutations or reduction of the proportion of ETV-resistant mutants. An ADV- and LMV-resistant mutant (rtA181T) emerged in 2 patients (11.7%). Conclusions: ADV plus LMV combination therapy suppresses ETV-resistant mutants in the viral population and significantly reduces serum HBV DNA levels in ETV-resistant CHB patients. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective. Following initial transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC), these tumors can frequently recur, making it important to determine the appropriate follow-up interval after initial response to TACE. We therefore assessed the time taken by new recurrent HCCs to double in volume after an initial response to TACE. Material and methods. This retrospective cohort study included 73 patients who achieved an initial response after TACE. After intrahepatic distant recurrence of HCC, dynamic CT scans were reviewed by two radiologists without clinical information, and the doubling time of new recurrent nodules was determined. The relationship between doubling time and clinical factors was also analyzed. Results. In 32 of the 73 patients, 40 intrahepatic distant recurrent (IDR) nodules were detected over a median period of 14 months (range 4–46 months). The 1-, 2- and 3-year cumulative IDR rates of patients were 27%, 45% and 65%, respectively. The doubling time of IDR HCC ranged from 20 to 104 days, with a median of 46 days. Over 90% of IDR HCCs had a doubling time of less than 3 months. The doubling time (median 108 days; range 51–129 days) of primary HCC in five patients for whom we had information regarding primary tumors was longer than that of recurrent nodules (median 28 days; range 24–90 days) in the same five patients ( P = 0.022). Conclusions. The median doubling time of IDR HCCs after an initial response was 47 days (range 20–104 days). These findings indicate that the appropriate follow-up interval for dynamic CT in patients with an initial response after TACE is less than 3 months. [ABSTRACT FROM AUTHOR]

Abstract: Background: Women who are taking antiviral agents and become pregnant have several options that include, continuing therapy, ceasing drugs, or switching to safer drugs. However, there are limited data on the outcome in pregnant women after withdrawal of antiviral agents. Objectives: We aimed to investigate the outcome of stopping antiviral agents in pregnant women with chronic hepatitis B virus (HBV) infection. Study design: In this single-center, retrospective cohort study, 12 pregnant patients who had received antiviral therapy for HBV and cease drugs after awareness of pregnancy between 2003 and 2010 were enrolled. We retrospectively studied virologic and biochemical flares during pregnancy and postpartum period. Results: Median age at pregnancy was 30.5 (range, 24–35) years, median duration of antiviral drug before pregnancy was 15.3 (range, 3.0–131.3) months, and median HBV DNA at withdrawal of therapy was 4.8 (range, 1.7–8.0) log10 copies/mL. Eight out of twelve patients (66.7%) had a viral rebound after stopping antiviral drugs during pregnancy. Severe hepatitis flares, defined as a 5-fold increase in serum alanine aminotransferase (ALT), were observed in six patients (50%) during pregnancy. However, all of these patients spontaneously recovered without an event of hepatic decompensation. High pretreatment ALT was associated with severe hepatitis flares after cessation of therapy during pregnancy. Five patients with at least 1-year treatment before pregnancy maintained low hepatitis activity after delivery. Conclusions: Pregnant women with high pretreatment ALT or those treated less than 1 year before pregnancy have high risk of severe hepatitis flares after cessation of antiviral agents. [Copyright &y& Elsevier]

Background/aims: Entecavir (ETV) is effective and safe antiviral agent against hepatitis B virus (HBV) in clinical and real-world setting but, most studies were performed in single institute or have limitation in patient's number. A large-scale nation-wide real-world surveillance study was carried out to investigate safety, efficacy and clinical effectiveness of ETV in Korean patients with chronic hepatitis B (CHB)., Methods: Between 2006 and 2012, 3,444 patients were enrolled from 132 Korean institutions. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs), as well as laboratory abnormalities. Efficacy, which consisted of change in HBV DNA and alanine aminotransferase (ALT), was evaluated in patients who had received at least 16 weeks of ETV treatment. Overall clinical effectiveness, based on improvement of ALT, HBV DNA and patient's symptoms, was evaluated by physicians., Results: Of the patients, 3,367 were evaluated for safety and 3,115 for efficacy and clinical effectiveness. Three hundred and eighty AEs were reported in 255 cases (7.57%), and 67 adverse drug reactions in 54 cases (1.6%). Serious AEs (SAE) were 19 events in nine cases (0.27%). Serious adverse drug reactions (SADR) were three events in two cases (0.06%), and unexpected SAE/SADR were three events in two cases (0.06%). Medical history and concomitant medications were factors inf luencing incidence rates of AEs. Overall clinical effectiveness rate was 96.53%, which was clinically assessed as marked improved or improved state., Conclusions: This study showed that ETV was well tolerated and clinically effective in Korean patients with CHB in a real-world nation-wide setting.

Background/aims: The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA)., Methods: Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry., Results: PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH., Conclusions: Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.

Background: Evaluating a change in the screening rate for hepatocellular carcinoma (HCC) is critical for understanding screening implementation, and whether targeted population groups are receiving proper screening. This study examined recent nationwide changes in HCC screening use among hepatitis B virus (HBV)-infected populations after the introduction of the Korean National Cancer Screening Program and predictors of screening adherence., Methods: We analyzed 165 and 276 participants ≥40 years of age who were hepatitis B surface antigen-positive from 2001 (14,936 participants) to 2010-2011 (9159 participants) Korea National Health and Nutrition Examination Surveys, respectively. Demographic data, socioeconomic factors, and HCC screening use were collected by means of self-reported questionnaires., Results: The rate of HCC screening within the previous 2 years increased significantly from 17.5% in 2001 to 40.3% in 2010-2011 (P < 0.0001). The rate of HCC screening use increased from 2001 to 2010-2011 in all study populations. Subjects who had a higher income status and were aware of their infection were more likely to have undergone recent HCC screening., Conclusions: This study showed a substantial increase in HCC screening in high-risk HBV-infected subjects from 2001 to 2010-2011. However, the HCC screening participation rate remained suboptimal despite the introduction of the nationwide screening program. Efforts should be made to identify high-risk individuals and increase attendance at HCC screening events among high-risk groups.

Background/aims: Data on the epidemiology of alcoholic cirrhosis, especially in Asian countries, are limited. We compared the temporal evolution of patterns of alcoholic and nonalcoholic cirrhosis over the last decade., Methods: We retrospectively examined the inpatient datasets of five referral centers during 2002 and 2011. The study included patients who were admitted due to specific complications of liver cirrhosis. We compared the causes of hospital admissions and in-hospital deaths between patients with alcoholic and nonalcoholic cirrhosis., Results: Among the included 2,799 hospitalizations (2,165 patients), 1,496 (1,143 patients) were from 2002, and 1,303 (1,022 patients) were from 2011. Over time, there was a reduction in the rate of hepatic encephalopathy (HE) as a cause of hospitalization and an increase in the rate of hepatocellular carcinoma. Deaths that were attributable to HE or spontaneous bacterial peritonitis (SBP) significantly decreased, whereas those due to hepatorenal syndrome (HRS) significantly increased over time in patients with alcoholic cirrhosis. However, in patients with nonalcoholic cirrhosis, hepatic failure and HRS remained the principal causes of in-hospital death during both time periods., Conclusions: The major causes of in-hospital deaths have evolved from acute cirrhotic complications, including HE or SBP to HRS in alcoholic cirrhosis, whereas those have remained unchanged in nonalcoholic cirrhosis during the last decade.

Aim: To investigate whether nonalcoholic fatty liver disease (NAFLD) affects coronary artery disease (CAD) and identify candidate mediators., Methods: Patients who underwent coronary angiography were consecutively recruited. The patients were classified into four groups by coronary artery stenosis: A, insignificant; B, one-vessel disease; C, two-vessel disease; and D, three-vessel disease. Abdominal ultrasonography was performed to determine the presence of a fatty liver and categorize by grade: 0, no evidence; 1, mild; 2, moderate; and 3, severe. We measured not only known CAD risk factors, but also serum insulin, HOMA-index, adiponectin, interleukin-6, tumor necrosis factor-α and high-sensitivity C-reactive protein levels., Results: Of the 134 patients who met the inclusion criteria, 82 (61.2%) had ultrasonographically diagnosed NAFLD. Among the 46 patients with CAD, 37 (80.4%) had evidence of a fatty liver. The two groups (A vs B-D) were significantly different in terms of age, total cholesterol, triglycerides, low-density lipoprotein levels and fatty liver. Coronary artery stenosis was strongly associated with fatty liver in a grade-dependent manner (P = 0.025). In binary logistic regression, NAFLD was a significant independent predictor of CAD (P = 0.03, OR = 1.685; 95%CI: 1.051-2.702). Among the candidate mediators, the serum adiponectin level showed a trend toward lowering based on CAD progression (P = 0.071)., Conclusion: NAFLD is an independent risk factor for CAD in a grade-dependent manner. Moreover, adiponectin might be related to the pathogenesis of NAFLD.

Background/aims: The aims of this study were (1) to identify the useful clinical parameters of noninvasive approach for distinguishing nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), and (2) to determine whether the levels of the identified parameters are correlated with the severity of liver injury in patients with NASH., Methods: One hundred and eight consecutive patients with biopsy-proven NAFLD (age, 39.8±13.5 years, mean±SD; males, 67.6%) were prospectively enrolled from 10 participating centers across Korea., Results: According to the original criteria for NAFLD subtypes, 67 patients (62.0%) had NASH (defined as steatosis with hepatocellular ballooning and/or Mallory-Denk bodies or fibrosis ≥2). Among those with NAFLD subtype 3 or 4, none had an NAFLD histologic activity score (NAS) below 3 points, 40.3% had a score of 3 or 4 points, and 59.7% had a score >4 points. Fragmented cytokeratin-18 (CK-18) levels were positively correlated with NAS (r=0.401), as well as NAS components such as lobular inflammation (r=0.387) and ballooning (r=0.231). Fragmented CK-18 was also correlated with aspartate aminotransferase (r=0.609), alanine aminotransferase (r=0.588), serum ferritin (r=0.432), and the fibrosis stage (r=0.314). A fragmented CK-18 cutoff level of 235.5 U/L yielded sensitivity, specificity, and positive and negative predictive values of 69.0%, 64.9%, 75.5% (95% CI 62.4-85.1), and 57.1% (95% CI 42.2-70.9), respectively, for the diagnosis of NASH., Conclusions: Serum fragmented CK-18 levels can be used to distinguish between NASH and NAFL. Further evaluation is required to determine whether the combined measurement of serum CK-18 and ferritin levels improves the diagnostic performance of this distinction.

Objectives: We investigated the pattern of serial HBV DNA levels in known cirrhosis patients and its impact on the development of hepatocellular carcinoma (HCC)., Methods: We analyzed a retrospective case/control study based on 352 HCC patients associated with HBV between 2005 and 2007. Prior to HCC development, 49 cirrhosis patients were tested for HBV DNA levels more than once a year (median 4 times) during the follow-up period. Ninety-eight consecutive cirrhosis patients without HCC, matched for age, sex and HBe Ag status were included as controls. Eighty-three patients in both groups had undergone antiviral therapy., Results: In cirrhosis, the most common HBV DNA pattern was fluctuating (33.3%), followed by persistently high (> or =10(4) copies/ml, 23.8%). Compared to a persistently low pattern (<10(4) copies/ml), the relative risks of HCC in patients with persistently high and fluctuating patterns were 2.650 and 1.475. At multivariate analysis, a persistently high pattern was an independent risk factor for HCC (hazard ratio 3.135). Patients with sustained HBV DNA suppression during antiviral therapy were less likely to develop HCC than those with viral breakthrough/nonresponse., Conclusions: This study showed that persistent suppression of HBV DNA is also important to prevent the development of HCC in known cirrhosis patients., (Copyright 2009 S. Karger AG, Basel.)

Background and Aims: The topographical distribution of hepatitis B core antigen (HBcAg) is related to the pathogenesis of liver damage caused by hepatitis B virus (HBV) infection. beta-catenin plays an important role in both intracellular adhesion and Wnt signaling transduction pathways. This study investigated the intrahepatic expression of HBcAg and beta-catenin in chronic HBV infection, and correlated the results with the degree of liver damage and viral replication., Method: Liver sections from 73 patients with chronic HBV infection were examined immunohistochemically for HBcAg and beta-catenin., Results: The distribution of HBcAg could be classified into four types: only nucleus (C-1), both nucleus and cytoplasm (C-2), only cytoplasm (C-3) and all negative for nucleus and cytoplasm (C-4). Significant differences in serum aminotransferase level, HBV DNA and necroinflammatory score were observed among the different distribution types, and as the distribution of HBcAg changed from C-1 to C-4, fibrosis stage and hepatitis B e antigen (HBeAg) negative/anti-HBe positive rate increased concurrently. The distribution of beta-catenin could be classified into two types: only membrane (B-1) and membrane with nucleus or cytoplasm (B-2). B-2 showed higher serum aminotransferase level and necroinflammatory score than B-1. Between B-1 and B-2, there was no significant difference in serum HBV DNA level or fibrosis stage., Conclusions: In chronic HBV infection, HBcAg distribution may change from C-1 to C-4 gradually, and in correlation with serum aminotransferase, and HBV DNA and HBeAg negative/anti-HBe positive rate. Nuclear or cytoplasmic distribution of beta-catenin, compared with exclusive membranous distribution of beta-catenin, is related to active hepatitis, but not viral replication.

Myxedema ascites caused by hypothyroidism is rare, so its diagnosis is often delayed and patients frequently receive unnecessary procedures such as liver biopsies and exploratory laparotomies. We report a 71-yr-old man with clinical ascites that was the first manifestation of hypothyroidism, and which resolved completely in response to thyroid hormone replacement therapy. To our knowledge, this is the first report of myxedema ascites in Korea. A review of the literature revealed 51 well-documented cases of myxedema ascites. Analyses of ascites from patients in this condition usually show high protein (>2.5 g/dL) and low white blood cell counts, with a high proportion of lymphocytes. A consistent feature is the good response to thyroid hormone replacement therapy, which has always led to resolution of the ascites. Myxedema ascites is thus rare but easy to treat; it should be borne in mind, especially if the ascites fluid has a high protein content.

Drug resistance remains a major problem during lamivudine treatment for patients with hepatitis B virus infection. Continuing or stopping lamivudine in patients with biochemical breakthrough is an issue that has not been investigated extensively. Particularly, HBeAg seroconversion and its durability achieved in these settings have never been studied so far. In this study, we compared the clinical outcomes including HBeAg seroconversion in hepatitis B e antigen (HBeAg)-positive patients who either continued or stopped lamivudine treatment after biochemical breakthrough. This was a retrospective cohort study of 73 consecutive patients with biochemical breakthrough followed up for at least 12 months. Of these, 35 (Group I) stopped and the remaining 38 (Group II) continued lamivudine therapy after breakthrough. During 12 months, there was a tendency towards higher rates of HBeAg seroconversion in Group I compared with Group II (P = 0.078). By multivariate analysis, age >or=45 years and acute exacerbation within 6 months of stopping lamivudine were the two independent predictors of HBeAg seroconversion for Group I (P = 0.034 and P = 0.012, respectively). There was no difference in the overall incidence of acute exacerbation and hepatic decompensation between the two groups (P = 0.333 and P = 0.555, respectively). Six patients (17.1%) in Group I developed hepatic decompensation, for which bilirubin >or=1.2 mg/dl was an independent predictor (P = 0.002). The therapeutic gain in continuing lamivudine for biochemical breakthrough is questionable. This study suggests that discontinuation of lamivudine may be an option in older patients with normal bilirubin level., ((c) 2005 Wiley-Liss, inc.)

Objective: The aim of this study was to evaluate retrospectively the long-term effects of lamivudine in 461 Korean patients with chronic hepatitis B who were treated for more than 12 months., Methods: The annual rates of virological response and breakthrough were examined and the predictive factors for post-treatment relapse in 114 patients who achieved hepatitis B e antigen (HBeAg) loss or seroconversion after lamivudine therapy were also analyzed., Results: During follow-up, the rates of HBeAg seroconversion after 1, 2, 3, 4 and 5 years of treatment were 22.9, 33.2, 47.6, 54.2 and 58.8%, respectively, while those for virological breakthrough at 1, 2, 3 and 4 years were 8.2, 41.7, 55.7 and 64.8%, respectively. Ninety-five patients (20.6%) had HBeAg seroconversion and 19 (4.1%) showed HBeAg loss alone with disappearance of hepatitis B virus DNA in serum. Seroconversion was higher with prolonged treatment in patients who had elevated serum alanine aminotransferase. The cumulative relapse rates in the seroconversion group were 52.0 and 55.7% 1 and 2 years after treatment, respectively. Age and the duration of additional treatment were significant predictive factors for post-treatment relapse. Patients aged 12 months after seroconversion had the lowest relapse rate (p < 0.001)., Conclusions: These results suggest that additional treatment for over 12 months after HBeAg seroconversion in younger patients may produce a better long-term outcome., (Copyright (c) 2005 S. Karger AG, Basel.)

To investigate the potential implication of the subtype of intestinal metaplasia in the progression to the gastric carcinoma, we analyzed the mutations of the p53 gene and microsatellite instability (MSI) both in the complete type (type I) and in the sulphomucin-secreting incomplete type (type III) intestinal metaplasia located adjacent to the gastric carcinoma. p53 mutations were observed in 13.3% of type I, in 6.6% of type III intestinal metaplasia, and in 40% of gastric carcinoma. The difference between p53 mutations observed in type I and type III intestinal metaplasia was not statistically significant. No identical mutation of the p53 gene was found in the intestinal metaplasia and carcinoma specimens from the patients. There was no case of intestinal metaplasia showing MSI. In gastric carcinomas, MSI was observed in six cases (40%). The cases harboring BAT-26 instability did not have the mutation of the p53 gene. These data suggest that intestinal metaplasia adjacent to gastric carcinoma, irrespective of its subtype, do not have the genetic alterations as showing in their carcinoma tissues.

Background: One of the major morphologic characteristics of hepatitis B is a hepatocellular regeneration which is induced by massive hepatocyte necrosis and associated with proliferative activity of hepatocytes. The purpose of this study is to document the proliferative activity of hepatocytes in various types of hepatitis B by immunohistochemical staining for proliferative cell nuclear antigen-labelling index (PCNA-LI) and electron microscopy., Methods: We studied 83 patients with hepatitis B: 11 cases of acute viral hepatitis, 24 cases of mild chronic hepatitis, 34 cases of severe chronic hepatitis with early cirrhosis and 14 cases of severe chronic hepatitis. The PCNA was tested by immunohistochemical staining using anti-PCNA antibody. Furthermore we evaluated the ultrastructure of acinus-forming hepatocytes (AFH) by electron microscopy., Results: The expression rate and labelling index of PCNA were 27.3% and 5.3 +/- 0.9% in acute viral hepatitis, 62.5% and 22.9 +/- 31.7% in mild chronic hepatitis, and then 47.1% and 14.1 +/- 24.2% in severe chronic hepatitis with early cirrhosis, respectively (Figure 1). By contrast, no detectable PCNA expression was noted in AFH. Electron microscopic findings showed that hepatocytes forming a rosette underwent marked degenerative changes with sinusoidal capillarization and increased fine strands of collagen fiber in portal area., Conclusion: The proliferative activity of hepatitis B was significantly decreased in severe chronic hepatitis containing AFH. This result suggested that differences in proliferative activity was associated with hepatic cell necrosis and AFH.