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To compare long-term survival after hepatic resection and transarterial chemoembolization of large solitary hepatocellular carcinomas (HCCs).Analysis of 91 and 68 consecutive patients with large (≥ 5 cm) solitary HCCs who underwent hepatic resection and transarterial chemoembolization, respectively, was performed. Overall survival and time to progression (TTP) were estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model. To control for treatment-selection bias, matched groups of patients were selected using a propensity score matching method, and survival analysis was repeated.During the follow-up period (median, 60.7 mo; range, 0.5-122.2 mo), 42 (46%) patients in the hepatic resection group and 35 (51%) patients in the transarterial chemoembolization group died. The 1-year, 3-year, and 5-year overall survival rates of the hepatic resection and transarterial chemoembolization groups were 91.1%, 80.0%, and 66.4% (hepatic resection group) and 89.8%, 72.8%, and 49.6% (transarterial chemoembolization group) (P = .023). TTP was significantly longer in patients who underwent hepatic resection (P.001). Hepatitis B surface antigen positivity and the absence of portal hypertension were independent predictors for favorable overall survival. For patients with platelet counts ≤ 100,000/mm(3), Child-Pugh score of 6, smaller HCCs (≤ 7 cm), or portal hypertension, hepatic resection and transarterial chemoembolization yielded similar overall survival rates. After propensity score matching, transarterial chemoembolization was comparable to hepatic resection in overall survival (P = .293), whereas TTP remained longer in patients who underwent hepatic resection (P = .001).Transarterial chemoembolization can lead to results comparable to hepatic resection in the treatment of large solitary HCCs, particularly in patients with clinically presumed portal hypertension.

Sorafenib is a systemic chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the anticancer effect of sorafenib in cancer stem cell‑like cells, such as side population (SP) cells, in HCC and to analyze the signaling pathway for drug‑resistance. To evaluate the anticancer effects of sorafenib, Huh7 and Huh‑BAT cells were treated with sorafenib, fluorouracil (5‑FU), and sorafenib plus 5‑FU. These cells were examined for growth rates, the SP fraction, sphere‑forming efficacy and expression of c‑Jun N‑terminal kinase (JNK) signaling molecules. Sorafenib and 5‑FU treatment decreased growth rates in Huh7 and Huh‑BAT cells; however, the treatments exerted different effects in SP cells and on the expression levels of JNK signaling molecules. Treatment with 5‑FU increased the SP cell number and upregulated the expression of JNK signaling molecules. By contrast, sorafenib decreased the SP cell number and downregulated the expression of JNK signaling molecules. No significant differences in sphere‑forming efficacy were observed subsequent to 5‑FU and sorafenib treatment in Huh7 and Huh‑BAT cells. These results indicate that sorafenib exerted anticancer effects in HCC and SP cells by targeting JNK signaling.

A uniform staging system for hepatocellular carcinoma (HCC) is needed. In this study, the discrimination abilities of HCC staging systems (American Joint Committee on Cancer [AJCC], Barcelona Clinic Liver Cancer [BCLC], Cancer of the Liver Italian Program, and Okuda stage) were compared during the course of untreated HCC.We included consecutive 80 patients diagnosed with HCC, but were not treated for HCC, at a single medical center in Korea. In addition, 177 treated patients matched by prognostic factors were included to evaluate the survival gain owing to locoregional treatment.The mean age of untreated patients was 58.7 years. During the observation period (median = 41.1 months), 72 patients died (median survival = 2.1 months; range = 1.6-33.7 months). Among various staging systems, the BCLC system had the best discrimination ability (linear trend χ2 = 16.35). Multivariate analysis indicated that the intrahepatic tumor classification (AJCC T classification) was an independent predictor of overall survival (OS) (P = 0.001). However, either node or metastasis classification failed to affect the OS significantly (both P 0.05). Patients undergoing intrahepatic tumor control with locoregional therapy showed prolonged survival in those patients with nodal involvement (hazard ratio = 0.315; P = 0.004) and extrahepatic metastasis (hazard ratio = 0.658; P = 0.258), respectively, after adjustment for independent prognostic factors. Compared with untreated patients, BCLC stage A and B patients had 1 year of survival gain but those with stage C and D did not, owing to locoregional therapy.The BCLC system had the best discrimination among untreated HCC patients. However, re-evaluation of the clinical importance of nodal and metastasis classification might be required.

Although oral nucleos(t)ide analogues can lead to suppression of serum hepatitis B virus (HBV) DNA to undetectable levels efficiently, they usually fail to achieve seroclearance of hepatitis B surface antigen (HBsAg), which indicates eradication of HBV infection. In this study, the efficacy of therapeutic vaccination in patients with chronic HBV infection was evaluated by comparing to the control patients. Patients who had achieved complete virologic response following oral nucleos(t)ide analogue treatment for at least 6 months were included. Vaccinated patients were given three intramuscular injections of hepatitis B vaccine that each contains 20 µg of HBsAg. The efficacy of vaccination was assessed by testing for HBsAg seroclearance. A total of 32 consecutive patients were analyzed, which included 15 vaccinated patients and 17 control patients. At month 6, 1 out of 15 vaccinated patients (6.7%) and 1 out of 17 control patients (5.9%) were determined to clear HBsAg from their sera (P = 1.000). A baseline HBsAg titer of ≤100 IU/mL tended to be predictive of HBsAg seroclearance, but the relationship was not significant (P = 0.097). During the follow-up period, virologic relapse occurred in 29 patients, and 9 patients developed hepatitis flare. The cumulative incidences of virologic relapse and hepatitis flare were similar between the vaccinated and control patients (P = 0.077 and P = 0.667, respectively). In conclusion, therapeutic HBV vaccination in patients who had stopped nucleos(t)ide analogue treatment showed limited efficacy for HBsAg seroclearance. To enhance the efficacy and safety of therapeutic HBV vaccination, rational patient selection and novel therapeutic approaches are needed.

Background The antioxidant mechanism of sevoflurane post-conditioning-induced neuroprotection remains unclear. We determined whether sevoflurane post-conditioning induces nuclear factor erythroid 2-related factor (Nrf2, a master transcription factor regulating antioxidant defence genes) and haemoxygenase-1 (HO-1, an antioxidant enzyme) expression, and whether protein kinase C (PKC) is involved in Nrf2 activation, in a rat model of transient global cerebral ischaemia/reperfusion (I/R) injury. Methods Eighty-six rats were assigned to five groups: sham (n=6), control (n=20), sevoflurane post-conditioning (two cycles with 2 vol% sevoflurane inhalation for 10 min, n=20), chelerythrine (a PKC inhibitor; 5 mg kg−1 i.v. administration, n=20), and sevoflurane post-conditioning plus chelerythrine (n=20). The levels of nuclear Nrf2 and cytoplasmic HO-1 were assessed 1 or 7 days after ischaemia (n=10 each, apart from the sham group, n=3). Results On day 1 but not day 7 post-ischaemia, Nrf2 and HO-1 expression were significantly higher in the sevoflurane post-conditioning group than in the control group. Chelerythrine administration reduced the elevated Nrf2 and HO-1 expression induced by sevoflurane post-conditioning. Conclusions Sevoflurane post-conditioning increased Nrf2/HO-1 expression via PKC signalling in the early phase after transient global cerebral I/R injury, suggesting that activation of antioxidant enzymes may be responsible for sevoflurane post-conditioning-induced neuroprotection in the early phase after cerebral I/R injury.

The emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P= 0.072 andP= 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.

Background & Aims Advanced liver fibrosis is associated with recurrence after curative resection of hepatocellular carcinoma (HCC). This study aimed to investigate whether noninvasive fibrosis indices could predict intrahepatic recurrence and death after curative resection of HCC. Methods Patients who underwent curative resection for hepatitis B virus (HBV)-related HCC between 2006 and 2010 at a single tertiary hospital were included. This study analysed the association of noninvasive fibrosis indices with recurrence and overall survival. Results A total of 303 patients were included. During a median follow-up period of 56.0 (interquartile range, 42.0–70.0) months, 151 (49.8%) patients experienced HCC recurrence and 54 (17.8%) died. Based on multivariate analysis, Forns index [hazard ratio (HR), 1.238; 95% confidence interval (CI), 1.097–1.398; P = 0.001] was independently associated with tumour recurrence after adjustment for anti-HBe positivity, histological cirrhosis, tumour size and number. Patients with Forns index

Background & Aims Hepatitis B virus (HBV) infection is the most serious risk factor for chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma. Recently, several genome-wide association studies (GWASs) identified important variants associated with the risk of CHB in Asian populations. Specifically, our previous GWAS identified the VARS2-SFTA2 gene region as one of the genetic risk loci for CHB. Methods To further characterize this association and to isolate possible causal variants within it, we performed an additional association study by genotyping more SNPs in the vicinity of the VARS2 and SFTA2 genes. In all, 14 SNPs of VARS2-SFTA2 were analysed among a total of 3902 subjects (1046 cases and 2856 controls). Results Logistic regression analysis revealed that six SNPs, including the previously reported rs2532932, were significantly associated with the risk of CHB (P = 1.7 × 10−10~0.002). Further linkage disequilibrium and conditional analysis identified two variants (rs9394021 and rs2517459) as new markers of genetic risk factors for CHB rather than the reported SNP from our previous study (rs2532932). To evaluate the cumulative risk for CHB based on all known genetic factors, genetic risk score (GRS) were calculated. As anticipated, the distribution of the number of risk alleles in cases vs. controls clearly differed according to the GRS. Similarly, the odds ratios (ORs) were increased (OR = 0.32–3.97). Conclusion Our findings show that common variants in the VARS2-SFTA2 gene region are significantly associated with CHB in a Korean population, which may be useful in further understanding genetic susceptibility to CHB.

Nonalcoholic fatty liver disease (NAFLD) is closely related to the metabolic syndrome, which is associated with an increased risk of various malignancies. In this study, we investigated the association between NAFLD and prostate cancer biochemical recurrence (BCR) after radical prostatectomy. Consecutive prostate cancer patients who underwent radical prostatectomy were enrolled from two hospitals in Korea and randomly assigned to the training (n=147) or validation set (n=146). The presence of NAFLD, BMI, preoperative prostate-specific antigen, and histological findings including Gleason score (GSc) were analyzed in regard to their association with BCR. NAFLD was diagnosed based on ultrasonography or unenhanced computed tomography images. BCR-free survival rates were calculated using the Kaplan–Meier method. In the training set, 32 (21.8%) patients developed BCR during a median follow-up period of 51 (inter-quartile range, 35–65) months. In the multivariate analysis, the presence of NAFLD (hazard ratio (HR), 0.36; 95% CI, 0.14–0.97;P=0.04) was an independent negative predictive factor of BCR after adjustment for pathological GSc. Applied to the validation set, the presence of NAFLD maintained its prognostic value for longer time-to-BCR (HR, 0.17; 95% CI, 0.06–0.49;P=0.001). In the subgroup analysis of patients with NAFLD, NAFLD fibrosis score was a single independent negative predictor for BCR (HR, 0.54; 95% CI, 0.30–0.98;P=0.04). Our study demonstrated that NAFLD may play a protective role against BCR after radical prostatectomy for prostate cancer. Further study is warranted to elucidate the mechanism of protective effect in patients with NAFLD.

The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n = 142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n = 233), and patients with LAM-R when starting ETV (group 3, n = 125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR] = 14.4, P < 0.001) but also in group 2 (HR = 5.0, P < 0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR = 13.0, P = 0.013) as well as group 3 (HR = 43.9, P < 0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were

Background The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde. We investigated possible involvement of these functional polymorphisms in other common complex-trait diseases. Methods The genetic effects of these two polymorphisms on hepatitis, asthma, type-2 diabetes mellitus (T2DM), and tuberculosis (TB) were examined in a Korean population. Results We demonstrated that the well-known functional polymorphism of a primary alcohol-metabolizing enzyme (ALDH2 Glu487Lys) has a strong genetic association with the risk of TB. The frequency of the minor allele (ALDH2*487Lys) was found to be much lower in TB patients (freq. = 0.099/n = 477) than among controls (freq. = 0.162/n = 796) (P = 0.00001, OR (95% confidential interval) = 0.57 (0.45-0.74)). Our data may indicate that TB was once an endemic disease, which exerted selection pressure for higher frequencies of ALDH2*487Lys in Asian populations. In addition, the calculated attributable fraction (AF) indicates that 39.5% of TB patients can attribute their disease to the detrimental effects of ALDH2Glu487Glu. Conclusion Our results suggest that this polymorphism is one of the genetic components of TB, at least in the Korean population.

Background and aimThe utility of fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET/CT) in initial staging of hepatocellular carcinoma (HCC) has yet to be fully explored. We assessed the usefulness of (18)F-FDG PET/CT in initial staging of HCC.MethodsA total of 457 consecutive patients initially diagnosed with HCC at Seoul National University Hospital between 2006 and 2012 were evaluated retrospectively to assess the impact of (18)F-FDG PET/CT on staging and compliancy with Milan criteria, relative to dynamic CT of liver and chest x-ray.ResultsSeven among the 457 patients studied showed a shift in Barcelona Clinic Liver Cancer [BCLC] stage (A → C: 6 patients; B → C: 1 patient) and 5 patients who had originally met Milan criteria no longer qualified. (18)F-FDG PET/CT had value in initial staging of early (stage A) or intermediate (stage B) HCC, as determined by dynamic CT of liver and BCLC or AJCC classifications, whereas BCLC stage 0 and stage C tumors were unchanged (PConclusionsIn initial staging of HCC, (18)F-FDG PET/CT provided additional information, impacting the patients with BCLC (stages A and B) and AJCC (T2 and T3) classifications. Its use might be thus appropriate for these patient subsets, especially if hepatic resection or liver transplantation is planned.

mRNA expression of urokinase and plasminogen activator inhibitor-1 in human crescentic glomerulonephritis Aims: Weak staining for urokinase-plasminogen activator (uPA), tissue type plasminogen activator (tPA), or plasminogen activator inhibitor-1 (PAI-1) confined to crescents has been described in a few cases of severe crescentic glomerulonephritis. We evaluated the molecular mechanism by which these proteins are increased or induced within crescents. Methods and results: We examined uPA, tPA and PAI-1 mRNA expression in 12 renal biopsies with crescentic glomerulonephritis, and in six control renal biopsies with no detectable abnormalities by RNA in-situ hybridization. The expressions of uPA, tPA and PAI-1 proteins were also assessed by immunofluorescence. To better determine the cellular origin of uPA and PAI-1 transcripts, CD68 protein was studied by immunohistochemistry on the same sections on which in-situ hybridization had been performed. In controls, there were very low level signals of uPA and PAI-1 mRNAs in a few glomerular epithelial cells (GECs). Specific signals of uPA and PAI-1 mRNAs were detected in the cells forming crescents in all the cases with crescentic glomerulonephritis. However, weak expression of mRNA for tPA was detected in two cases only. Immunostaining for uPA and PAI-1 was positive in some but not all, cases of crescentic glomerulonephritis. A double-labelling study showed that the signal for PAI-1 and uPA mRNAs was mainly in CD68− cells. Conclusions: Local accumulation of uPA or PAI-1 in crescents is associated with enhanced mRNA expression of these proteins. The up-regulation of PAI-1 mRNA by GECs, in particular, could play a major role in the formation of persistent fibrin deposits and progression of the lesions in crescents. Whether up-regulation of uPA is an epiphenomenon or plays a pathogenic role in the formation of crescents remains to be clarified.

Background Hepatopulmonary syndrome (HPS) refers to the association of hypoxemia, intrapulmonary shunting and chronic liver disease. But there is no clear data about the prevalence of HPS in postnecrotic liver cirrhosis by hepatitis B virus (HBV), the most common cause of liver disease in Korea. The aim of this study was to investigate the prevalence of HPS in poorly compensated postnecrotic liver cirrhosis by HBV, and the correlation of the hepatopulmonary syndrome with clinical aspects of postnecrotic liver cirrhosis by HBV. Methods: Thirty-five patients underwent pulmonary function test, arterial blood gas analysis and contrast-enhanced echocardiography. All patients were diagnosed as HBV-induced Child class C liver cirrhosis and had no evidence of intrinsic cardiopulmonary disease. Results: Intrapulmonary shunt was detected in 6/35 (17.1%) by contrast-enhanced echocardiography. Two of six patients with intrahepatic shunts had significant hypoxemia (PaO2 < 70 mmHg) and four showed increased alveolar-arterial oxygen gradient over 20 mmHg. Only cyanosis could reliably distinguish between shunt positive and negative patients. Conclusions: The prevalence of intrapulmonary shunt in poorly compensated postnecrotic liver cirrhosis by HBV was 17.1% and the frequency of hepatopulmonary syndrome was relatively low (5.7%). ‘Subclinical’ hepatopulmonary syndrome (echocardiographically positive intrapulmonary shunt but without profound hypoxemia) exists in 11.4% of cases with poorly compensated postnecrotic liver cirrhosis by HBV. Cyanosis is the only reliable clinical indicator of HPS of HBV-induced poorly compensated liver cirrhosis. Further studies are required to determine if the prevalence and clinical manifestations of HPS varies with etiology or with geographical and racial differences.

PURPOSE To evaluate the incidence of, predisposing factors for, and clinical outcome of liver abscess developing in patients with hepatic tumors after transcatheter oily chemoembolization (TOCE). MATERIALS AND METHODS During the past 6-year period, 2,439 patients with hepatic tumors underwent a total of 6,255 TOCE procedures. With a retrospective review of medical records, the authors evaluated the occurrence of liver abscess, the statistical significance of potential predisposing factors including portal vein obstruction, metastatic tumors, biliary abnormalities (type 1, simple biliary obstruction; type 2, status prone to ascending biliary infection), malignant gastrointestinal mucosal lesions, and additional gelatin sponge particle embolization in liver abscess formation, and the clinical outcome of abscess. RESULTS Fifteen liver abscesses occurred in 14 patients (0.2%). Liver abscesses developed in three of 987 (0.3%) TOCE procedures for portal vein obstruction, three of 114 (2.6%) procedures for metastatic tumors, one of 49 (1.8%) for type 1 biliary abnormality, four of 55 (7.4%) for type 2 biliary abnormality, two of 18 (11.1%) for malignant gastrointestinal mucosal lesion, and nine of 2,108 (0.4%) for additional gelatin sponge particle embolization. Univariate and multivariate statistical analysis showed that type 2 biliary abnormality was a significant predisposing factor. The mortality related to liver abscess occurred in two patients (13.3%). Thirteen liver abscesses were successfully treated with parenteral antibiotics and percutaneous catheter drainage. However, irreversible deterioration of liver function occurred in two patients. Two of nine further TOCE procedures in three patients caused recurrent septicemia and liver abscess. CONCLUSION The biliary abnormality prone to ascending biliary infection was the most important predisposing factor to the development of liver abscess after TOCE. Postembolic liver abscess could be effectively managed with percutaneous catheter drainage.

Korea has been one of the endemic areas of hepatitis B virus (HBV; exclusively genotype C) infection since ancient times. The epidemiology of HBV in Korea is easily expected to have changed over the last two decades owing to the high coverage rate of universal HBV vaccination. The main mode of hepatitis C virus (HCV) infection may have been effectively blocked since 1992 when compulsory blood screening for anti-HCV was implemented, and consequently, the prevalence of anti-HCV is also expected to have markedly decreased during the last two decades. This review will briefly describe what really happened during the last couple of decades in the epidemiology of HBV and HCV and in the incidence and mortality rates of liver cirrhosis (hepatic failure) and hepatocellular carcinoma in Korea. How to cite this article Lee H-S. Viral Hepatitis in Korea: Past, Present, and Future. Euroasian J Hepato-Gastroenterol 2016;6(1):62-64.

Treatment strategies for entecavir (ETV)-resistant chronic hepatitis B (CHB) patients are not yet well established. The aim of this study was to evaluate overall antiviral efficacy and to compare the efficacy of combination therapy with adefovir (ADV) plus nucleoside analogues (lamivudine [LAM], telbivudine [LdT], or ETV) in patients infected with LAM- and ETV-resistant hepatitis B virus (HBV) variants. Virologic, biochemical, and serologic responses during combination therapy with ADV plus nucleoside analogues were assessed. Propensity score analysis was used to select a matched group of patients for the comparison of rescue therapy regimens. A total of 67 consecutive patients were analyzed. Complete virologic suppression was achieved in 27 patients. The overall cumulative incidence of complete virologic suppression at month 24 was 47.4%: 44.3% in the LAM or LdT plus ADV group and 51.4% in the group given ETV and ADV. There was no significant difference between these two groups ( P = 0.234). The cumulative incidences of complete virologic suppression were still comparable between the two groups selected and matched using the propensity score model ( P = 0.419). Virologic breakthrough was observed in 9 patients, and rtA181V substitution was newly detected in one patient. Hepatitis B e antigen (HBeAg) negativity and lower baseline HBV DNA level were associated with complete virologic suppression in univariate analysis. In multivariate analysis, lower baseline HBV DNA level remained an independent predictor. In conclusion, combination therapy with ADV plus nucleoside analogues fails to show sufficient antiviral efficacy in CHB patients with resistance to both LAM and ETV. Further study is warranted to evaluate the efficacy of a more potent tenofovir-based regimen in such patients.

We have recently developed an in vitro differentiation model of immortalized non-transformed human hepatocytes using butyrate, and observed the induction of inducible NO synthase (iNOS). In this study, we analyzed the effect of NO on the urea-synthetic capacity of these cells. The inhibition of iNOS during butyrate treatment significantly increased the urea-synthetic capacity as compared to that of butyrate treatment alone, possibly through the further induction of ornithine transcarbamylase expression. Therefore, the inhibition of NO production might be useful for obtaining more differentiated hepatocytes in the process of in vitro induction of hepatocyte-specific differentiation.

There is a need to develop human hepatocyte cell lines which retain both replicating capacity and highly differentiated functions to facilitate the development of an efficient bioartificial liver. The present study was undertaken to differentiate, using sodium butyrate, the actively replicating immortalized human liver cell line. The effects of butyrate on cell growth and cell cycle were analyzed, and the albumin synthesis, cytochrome P450 and ammonia-detoxifying activity of the butyrate-treated cells were measured. Butyrate treatment resulted in G2/M arrest of the cell cycle and polygonal changes in the cell morphology. Neither the control nor the butyrate-treated cells showed transformed characteristics. Butyrate treatment increased the amount of albumin secretion, cytochrome P450 activity, and the urea production rate of the cells. The present study provides non-transformed human hepatocytes, which can replicate unlimitedly and then restore differentiated hepatocyte-specific functions by butyrate, and therefore, have applications for the development of an efficient bioartiflcial liver

The positive predictability of anti-HCV ELISA is low, especially, in blood donors and in healthy populations. False positive anti-HCV results pose some difficulties in medical practice and in blood screening. The aim of this study was to identify the factors associated with true hepatitis C virus (HCV) infection among anti-HCV ELISA-positives. A case-control analysis was conducted using 354 subjects who were positive for anti-HCV ELISA. All subjects were tested for true HCV infection using the reverse transcriptase polymerase chain reaction (RT-PCR). Tests for serum alanine aminotransferase (ALT), fasting glucose, HBsAg, anti-HBc antibody, alpha-fetoprotein, platelet count and ultrasound of liver were also performed. Epidemiological data were obtained by self-administered questionnaires. Out of 354 subjects, 202 (57.1%) were positive for HCV by RT-PCR and 152 were negative and used as the control group. In multivariate analysis, blood transfusion (odds ratio, OR 2.3, 95% confidence interval, CI 1.3-4.0), elevated ALT (OR 2.2, 95% CI 1.2-4.3) and higher anti-HCV ELISA ratios (more than 3; OR 1.7, 95% CI 1.3-2.1) were associated with true HCV infection. Thrombocytopenia was also associated with the presence of HCV in univariate analysis. These results suggest that a history of blood transfusion, elevated ALT and a high score on anti-HCV ELISA ratios are associated with true HCV infection among anti-HCV ELISA-positives.

Liver transplantation has now become a favored option for patients with early-stage hepatocellular carcinoma (HCC) with or without impaired hepatic function as a complication of underlying cirrhosis. To overcome the persistent donor organ shortage, the use of adult-to-adult living donor liver transplantation (LDLT) has recently increased, especially in Asian countries. In the use of LDLT, several controversies remain including the safety of living donation and expanding the current Milan criteria. Most physicians agree that criteria for transplanting patients with HCC should be expanded beyond the Milan criteria because the Milan criteria miss a number of patients who may benefit from LDLT; however, the expanded criteria proposed were different (the size and number of HCCs and the biologic markers) from one center to the other. When we consider LDLT as a treatment option for patients with HCC, donor safety should be kept in mind first, and the wishes of both patient and donor should be weighed against the potential (if small) risk for the donor. In contrast to deceased donor liver transplantation, the benefit of LDLT is better appreciated in terms of gain in life expectancy than in terms of survival when the wishes of both patient and donor outweigh the donor risk. Further research on the predictors of benefit of LDLT to HCC patients other than the size and number of HCC such as molecular profiling of HCC are necessary to finally reach a consensus.

BACKGROUND Although transmission of hepatitis C virus (HCV) through parental exposure is well documented, it is still controversial whether familial clustering of HCV occurs. METHODS To investigate risk factors for HCV infection, 109 cases and 84 non-infected controls were studied. In addition, 250 family members (104 men, 146 women) of cases and 170 family members of controls (64 men, 106 women) were tested for HCV infection using an anti-HCV antibody, alanine aminotransferase (ALT), and reverse transcribed polymerase chain reaction (RT-PCR). RESULTS In the case-control analysis, people aged > or =60 were almost three times more likely to be infected by HCV than those aged

Background Primary liver cancer is an important health problem in Korea, where hepatitis B virus (HBV) infection is prevalent. The authors conducted a prospective cohort study to evaluate the protective effect of HBV vaccination against liver cancer in adults. Methods A total of 370 285 males aged 3*30 comprised the study population. They were clinically free of liver diseases, and had not been vaccinated against HBV at enrolment. The results of HBV surface antigen (HBsAg) and antibody to HBsAg (antiHBs) marker positivity and those of the vaccination programme which took place during 1985 were used for the construction of the cohort. About 5% (n = 18 914) were HBsAg positive, 78 094 were anti-HBs positive, and 273 277 were negative for both. Among the candidates for HBV vaccination (n = 273 277), 35 934 (13.2%) people had been vaccinated against HBV during 1985. Cases of liver cancer were ascertained by record linkage and from medical records covering 1986-1989. A multivariate log-linear model was used to test statistical significance and to estimate relative risks (RR). Results The total follow-up period was 1 404 566 person-years, with an average of 3 years and 10 months. A total of 302 incident cases were ascertained. The overall incidence rate of liver cancer was 21.7 per 100 000 person-years. With reference to the incidence level among the unvaccinated and uninfected, the RR of primary liver cancer among the chronically infected and that of the unvaccinated and infected was 18.1 (95% CI: 14.2-22.9) and 0.34 (95% CI: 0.19-0.60), respectively. The RR among the vaccinated group was 0.58 (95% CI : 0.31-1.09). Conclusions This study suggested that artificial immunization through HBV vaccination, even in adulthood, reduces the risk of liver cancer. It might also offer a practicable means of primary prevention, especially in areas with hyperendemicity of HBV infection.

The iso-enzyme pattern of cytochrome P450 was shown to be related to the development of chemically induced hepatocellular carcinoma (HCC) in rats, which is accelerated by chronic alcohol ingestion. Our study was designed to investigate the association of cytochrome P450 2E1 (CYP2E1) genetic polymorphisms with the susceptibility to HCC in humans with and without chronic alcohol ingestion. We enrolled 171 male patients (108 Korean and 63 Japanese) with HCC and 31 age- and sex-matched healthy Korean subjects with no evidence of liver disease or cancer in any organ. Genotypes in the 5'-flanking region of the CYP2E1 gene were determined by restriction fragment length polymorphisms using 2 endonucleases: Pst I and Rsa I. Allelic frequencies in the CYP2E1 5'-flanking region in the Korean control population were 83.5% and 16.5% for allele c1 and c2, respectively. The frequencies of genotypes with the c2 allele (c1/c2 and c2/c2) were compared with those of genotypes without c2 (c1/c1) among HCC patients and controls, according to the pattern of alcohol consumption. There was no significant association between HCC risk and genotypes c1/c2 and c2/c2 either in all HCC patients or in HCC patients of different ethnic groups. Habitual drinkers with HCC, especially among Koreans, were more likely to carry genotype c1/c2 and c2/c2 (odds ratio = 3.0) than non-habitual drinkers (odds ratio = 1.2); however, the difference was not statistically significant. Even when patients were restricted to those without hepatitis B surface antigen and antibodies against hepatitis C virus but with a history of chronic alcohol ingestion, there was still no increased risk of HCC in those with genotypes c1/c2 and c2/c2. We conclude that there is a lack of association of the polymorphisms of CYP2E1 with the risk of HCC in humans.

Objectives The relationship between HCV genotype and the development of more serious liver disease has not been clearly established. This study was to investigate the distribution pattern of HCV genotypes in Korea and their relationship to the viremic level and to progression of chronic liver disease. Methods Study population was 217 patients with type C chronic liver disease. They were divided into 4 groups: 83 patients with near-normal ALT (group 1), 64 patients with elevated ALT (group 2), 20 patients with decompensated liver cirrhosis (group 3) and 50 patients with hepatocellular carcinoma (group 4). HCV genotypes were determined by reverse transcription polymerase chain reaction (RT-PCR) using mixed primer sets, and then the fidelity of genotyping was confirmed by cloning and sequencing. HCV RNA concentration was measured by quantitative competitive RT-PCR for 23 patients in group 2. Results The genotypes could be determined in 166 (76%) out of 217 patients. Type 1b and type 2a were predominantly occurring over the other types in somewhat similar frequency (45% and 51%, respectively). The genotype distribution of type 1b and 2a among four different groups showed 42% and 54% in group 1, 49% and 45% in group 2, 53% and 47% in group 3 and 41% and 57% in group 4; thus there was no significant difference in genotype distribution among 4 different disease groups. However, the viremia levels in patients with genotype 1b infection were significantly higher than those with genotype 2a. Conclusion Genotype 2a infection is as prevalent as genotype 1b in Korea, and genotype 2a infection may pose no less risk for progression of disease despite lower replication level than genotype 1b infection.

Insulin like-growth factor-1 (IGF-1) reflects hepatic synthetic function and plays a major role in the development and progression of various cancers. In the present study, we investigated whether baseline serum IGF-1 levels predict time-to-progression (TTP) and overall survival (OS) in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE). A total of 155 consecutive treatment-naive patients with HCC who had undergone TACE as initial treatment were included from a prospective cohort. Baseline serum IGF-1 levels were analyzed with regard to their associations with disease progression and survival. During a median follow-up period of 41.8 months, patients with low IGF-1 levels showed significantly shorter TTP (median, 6.0 months; 95% confidence interval [CI], 4.5–7.6) than patients with high IGF-1 levels (median, 16.5 months; 95% CI, 4.9–28.1; p = 0.003). In the multivariate analysis, BCLC stage, serum vascular endothelial growth factorlevels, and IGF-1 levels were independent risk factors for disease progression. The hazard ratio (HR) of progression for each 10 ng/mL decrease in IGF-1 level was 1.072 (95% CI, 1.029–1.117; p = 0.001). Furthermore, together with tumor size, stage, and treatment response, IGF-1 levels were an independent predictor of poorer survival (for each 10 ng/mL decrease in IGF-1 level; HR, 1.057; 95% CI, 1.001–1.115; p = 0.045). In conclusion, low baseline IGF-1 levels independently correlated with shorter TTP and poorer OS in patients with HCC who underwent TACE.

Single nucleotide polymorphisms (SNPs) in microRNA (miR)-196a-2 have been suggested to contribute to susceptibility to various human cancers. The aim of this study was to determine whether polymorphisms of miRNA-196a-2 affect the clinical outcomes of hepatitis B virus (HBV) infection in Korean patients. Genotyping was performed for 1,439 Korean patients with either past or present HBV infection, including 404 control subjects who underwent spontaneous recovery and 1,035 subjects with chronic HBV (313 cases of chronic hepatitis B, 305 cases of cirrhosis of the liver, and 417 cases of hepatocellular carcinoma [HCC]). Genotyping results revealed that the polymorphism rs12304647AC, which lies in the pri-miRNA region of miR-196a-2, has a significant minor allele frequency (0.210). Logistic analysis revealed that the rs12304647AC SNP was associated with a significant protective effect against HCC in patients with chronic hepatitis (odds ratio [OR] = 0.70, P = 0.005 in a codominant model; OR = 0.73, P = 0.03 in a dominant model; OR = 0.31, P = 0.004 in a recessive model), and in the patients with cirrhosis (OR = 0.63, P = 0.0009 in a codominant model; OR = 0.66, P = 0.01 in a dominant model; OR = 0.25, P = 0.001 in a recessive model). A Cox relative hazards model with adjustments for age, gender, HBeAg status, and cirrhosis revealed that rs12304647AC retained its association with HCC in a codominant model (relative hazards [RH] = 1.14, P = 0.05) and in a recessive model (RH = 1.44, P = 0.03). However, the miR-196a-2 rs12304647AC SNP had no association with HBV clearance. In conclusion, the miR-196a-2 rs12304647 CC genotype had a protective effect against development of HCC in comparison to the AA or AC genotypes in patients with chronic hepatitis and cirrhosis.

The aims of this study were to investigate whether acid suppressive therapy increases the risk of spontaneous bacterial peritonitis (SBP) and to define factors associated with mortality in cirrhotic patients with SBP.Cirrhotic patients who had undergone paracentesis after hospitalization were included. Those patients were divided into two groups according to the presence or absence of SBP. Factors associated with the development of SBP were analyzed. Mortality rates during hospitalization or within 30 days after SBP and the factors associated with mortality were also analyzed.A total of 1140 patients (median age, 62; men, 75%; model for end-stage liver disease [MELD] score, 17) were included. Five hundred thirty-three patients were identified as having SBP. In the logistic regression, the use of histamine-2 receptor antagonists, the use of proton pump inhibitors (PPIs), a high admission MELD score, and old age were associated with the development of SBP. The use of PPIs within 30 days (adjusted odds ratio [aOR] 1.960; 95% confidence interval [CI] 1.190-3.227; P = 0.008), a higher admission MELD score (aOR 1.054; 95% CI 1.032-1.076; P0.001), and hepatocellular carcinoma (aOR 1.852; 95% CI 1.256-2.730; P = 0.002) were associated with mortality after SBP.Acid suppressive therapy is associated with the development of SBP in cirrhotic patients with ascites. The use of PPIs is associated with mortality after SBP independent of the severity of the underlying liver disease in our retrospective cohort study.

The hydrophobic bile acid, deoxycholic acid (DC), can induce apoptosis in hepatocytes. The roles of DC and its transporter are not yet established in hepatocellular carcinoma (HCC) cells. We investigated DC-induced alterations in HCC cell growth, with a particular focus on the effect of the expression of bile acid (BA)-transporting Na(+)-dependent taurocholic cotransporting polypeptides (NTCPs).We determined NTCP expression in four human HCC cell lines: Huh-BAT, Huh-7, SNU-761, and SNU-475. NTCP expression and apoptotic signaling cascades were examined by immunoblot analyses. Cell viability was assessed using the 3,4-(5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assay. Wound healing and invasion assays were performed to evaluate cell migration and invasion abilities. Real-time polymerase chain reaction was performed to measure IL-8 expression levels. Nuclear factor kappa B (NF-κB) activity was evaluated by enzyme-linked immunosorbent assay.The HCC cell lines revealed varying NTCP expression levels, and DC treatment had dual effects, depending on NTCP expression. DC induced apoptosis in NTCP-positive HCC cells, especially under hypoxic conditions. In NTCP-negative HCC cells, simultaneous treatment with DC and cyclooxygenase inhibitor markedly decreased aggressive cellular behaviors via the inhibition of NF-κB/COX-2/IL-8 pathways.Hydrophobic bile acid offers therapeutic potential for patients with advanced HCC via different mechanisms depending on NTCP expression levels within the tumor.

BACKGROUND/AIMS The production of high-sensitivity C-reactive protein (hs-CRP) may be affected by hepatic function, and the clinical importance of hs-CRP in patients with liver cirrhosis is still not clear. The aim of this study was to evaluate the clinical implications of hs-CRP in cirrhotic patients with spontaneous bacterial peritonitis (SBP). METHODS We retrospectively investigated 336 consecutive patients treated for SBP from 2007 to 2012. The relationship between serum hs-CRP and the result of the treatment was assessed. RESULTS A response to antibiotics was observed in 182 patients (54.2%), and 126 patients (37.5%) died of SBP. The initial hs-CRP (odds ratio=1.061, P=0.016), coexistent hepatocellular carcinoma, and Child-Pugh (CP) score were independent prognostic factors for high in-hospital mortality. Serum hs-CRP level was also an independent predictor of lower antibiotic response rate (odds ratio=0.916, P

Objectives The impact of characteristics of neighbourhood environment on physical activity and obesity-related diseases is still the subject of debate. This study aimed to explore the impact of urban neighbourhood environment on physical activity and obesity-related diseases. Study design Cross-sectional study. Methods Individuals who participated in the 2009 national health-screening programme, submitted all necessary information, and had lived in Community 1 (Haengdang) or Community 2 (Ilsan) for at least 2 years ( n = 16,178) were selected for inclusion in this study. Anthropometric measures were taken and physical activity was assessed using a short questionnaire. Results No significant difference in the trigger factors for walking, including the amount of neighbourhood park space, number of shopping malls, and distance between the community and shopping malls, was found between the two communities. However, Community 2 had a better street environment than Community 1. Participants who lived in Community 2 were more physically active [adjusted odds ratio (OR) 1.31, 95% confidence interval (CI) 1.16–1.48] and walked more regularly (adjusted OR 1.09, 95% CI 1.02–1.17) than participants who lived in Community 1, and were less likely to have abdominal obesity (adjusted OR 0.83, 95% CI 0.77–0.91), hypertension (adjusted OR 0.88, 95% CI 0.80–0.97) and diabetes (adjusted OR 0.86, 95% CI 0.75–0.99). However, the risk of dyslipidaemia, especially in terms of low-density lipoprotein cholesterol, was higher in Community 2. Conclusions These results suggest that a walkable environment has a positive influence on hypertension and diabetes, and physical activity is the possible mechanism for this association. A walkable environment may function as an important tool for health promotion in urban areas.

Summary Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV-based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed-effects model. HBV DNA levels were also compared between the five groups during the 96-week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P

Purpose: Insulin-like growth factor-I (IGF-I) reflects hepatic synthetic function and plays an important role in the development and progression of various cancers. In this study, we investigated whether pretreatment serum IGF-I levels predict time-to-recurrence (TTR) and overall survival (OS) in patients with early-stage hepatocellular carcinoma after curative treatment. Experimental Design: Consecutive patients with hepatocellular carcinoma who had undergone surgical resection, radiofrequency ablation, or percutaneous ethanol injection as curative treatments of early hepatocellular carcinoma were included from two prospective cohorts and the training set (n = 101) and the validation set (n = 91) were established. Serum samples were collected before treatment and the levels of IGF-I and IGF-binding protein-3 (IGFBP-3) were analyzed with regard to their associations with recurrence and survival. Results: In the training set, patients with low IGF-I levels showed significantly shorter TTR [median, 14.6 months; 95% confidence interval (CI), 1.8–27.5] than patients with high IGF-I levels (median, 50.8 months; 95% CI, 36.9–64.7; P < 0.001) during a median follow-up period of 52.4 months. In the multivariate analysis, low levels of IGF-I were an independent predictor of recurrence (HR, 2.49; 95% CI, 1.52–4.08; P < 0.001). Furthermore, together with high-serum α-fetoprotein and multiple tumors, low levels of IGF-I remained an independent predictor of poorer survival (HR, 8.00; 95% CI, 1.94–33.01; P = 0.004). Applied to the independent validation set, low-serum IGF-I levels maintained their prognostic value for shorter TTR and OS. Conclusions: Low-baseline IGF-I levels independently correlated with shorter TTR and poorer survival in patients with early-stage hepatocellular carcinoma after curative treatment. Clin Cancer Res; 19(15); 4218–27. ©2013 AACR.

Liver fibrosis is associated with the deposition of the extracellular matrix, and hepatic stellate cells (HSCs) are the major source of these matrix proteins. Guggulsterone has recently been shown to induce apoptosis in several cell lines. Thus, the aim of this study was to evaluate whether guggulsterone has antifibrotic activities by reducing the activation and survival of HSCs.Apoptotic and fibrosis-related signaling pathways and nuclear factor kappa B (NF-κB) activity were explored in LX-2 cells, an immortalized human HSC line, and in a mice model of liver fibrosis.Guggulsterone suppressed LX-2 cell growth in a dose- and activation-dependent manner. This growth suppression was due to the induction of HSC apoptosis, which was mediated by the activation of c-Jun N-terminal kinase and mitochondrial apoptotic signaling. Additionally, guggulsterone regulated phosphorylation of Akt and adenosine monophosphate-activated protein kinase, which were subsequently proven responsible for the guggulsterone-induced HSC growth suppression. Guggulsterone inhibited NF-κB activation in LX-2 cells, which is one of the major mediators in HSC activation. Indeed, guggulsterone decreased collagen α1 synthesis and α-smooth muscle actin expression in these cells. Compared with the control mice or mice treated with a low dose of guggulsterone, high dose of guggulsterone significantly decreased the extent of collagen deposition and the percentage of activated HSCs undergoing apoptosis.These results demonstrate that guggulsterone suppressed HSC activation and survival by inhibiting NF-κB activation and inducing apoptosis. Therefore, guggulsterone may be useful as an antifibrotic agent in chronic liver diseases.

Treatment of cirrhotic patients with spontaneous peritonitis using antibiotics occasionally fails. Fungal infections may be one of the causes of antibiotic treatment failure in such patients. In this study we evaluated the clinical significance and characteristics of spontaneous fungal peritonitis (SFP). Consecutive cirrhotic patients with spontaneous peritonitis treated between 2000 and 2005 at a tertiary care center in Seoul, Korea, were included. We analyzed the clinical characteristics and the prognosis of SFP patients compared with patients with spontaneous bacterial peritonitis (SBP). During the study period 416 patients developed spontaneous peritonitis and 15 (3.6 %) had SFP. Compared with patients with SBP, nosocomial peritonitis (peritonitis that developed after hospitalization for >72 h) was more common and the Child–Pugh score was higher in SFP patients (both, P < 0.01). Ten patients were infected with Candida spp. (C. albicans, 8; C. tropicalis, 1; C. glabrata, 1), and 5 with Cryptococcus neoformans. Eleven patients were co-infected with bacteria that were susceptible to the antibiotics administered. Only 5 patients were treated using appropriate anti-fungal agents. The 1-month mortality rate for SFP patients was 73.3 % (11 out of 15; median time to death, 2 days [range, 0–22]), which was significantly higher than patients with SBP alone (28.7 %, P = 0.0007). SFP is severe complication related to high mortality in cirrhotic patients. A longer admission and a higher Child–Pugh score may be risk factors. Immediate anti-fungal treatment is warranted in patients with spontaneous peritonitis, once fungus is found in the ascitic fluid.

Background. Spiral computed tomography (CT) allows imaging of the liver during the peak contrast material levels due to the capability of fast data acquisition. The objective of this study was to evaluate the usefulness of two-phase spiral CT in the differential diagnosis of focal hepatic tumors. Methods. One hundred two patients who had hepatic tumors (211 nodules ; 149 hepatocellular carcinomas [HCCs], 36 metastases, and 26 hemangiomas) underwent two-phase spiral CT with 10-mm collimation at 10 mm/second table speed and 120 mL of contrast material injected at the rate of 3 mL/second. Computed tomography images of the hepatic arterial phase and late (equilibrium) phase were obtained at 35-second and 180-second delays, respectively. The enhancement patterns of tumors were divided into six types and were compared with the attenuation of surrounding liver parenchyma : totally high, peripherally high, centrally high, mixed, iso, and low. Results. The common enhancement patterns of HCC in two-phase spiral CT were totally high in the arterial phase and low (n = 63, 42%) or iso (n = 28,19%) in the late phase. Metastasis showed peripherally nonnodular high attenuation (n = 9, 25%) or low attenuation (n = 9,25%) in the arterial phase and low attenuation in the late phase, followed by totally high attenuation in the arterial phase and iso in the late phase (n = 6, 17%). Hemangiomas showed totally or peripherally nodular enhancement in the arterial and late phases (n = 23, 89%). In distinguishing hemangiomas from malignant tumors, totally high or peripherally nodular high attenuation in the late phase was the most useful contrast enhancement pattern (96% of hemangioma vs. 0% of malignant tumors). In distinguishing HCCs from metastases, a combination of contrast enhancement pattern of totally high attenuation in the arterial phase and low in the late phase was the most useful contrast enhancement pattern (42% of HCCs vs. 0% of metastases). The predictability of differentiation between hemangiomas and malignant tumors and between HCCs and metastases was 99% and 90% with spiral CT, respectively. Conclusions. Two-phase spiral CT is useful in the differential diagnosis of focal hepatic tumors with evaluation of contrast enhancement patterns.

Objectives The present study was conducted to evaluate the prognostic significance of the absence of serum HBV DNA by polymerase chain reaction (PCR) after spontaneous HBeAg/anti-HBe seroconversion and concurrent or subsequent biochemical remission. Methods We prospectively investigated the reactivation rates in 28 chronic hepatitis B patients according to the positive or negative serum HBV DNA test by PCR. The sera drawn at a mean period of 4.4 months after normalization of alanine aminotransferase (ALT) were analyzed by PCR-Southern blot hybridization to detect HBV DNA, and then the patients were divided into two groups according to the presence (n = 14) or absence (n = 14) of HBV DNA in the sera. Results The cumulative reactivation rates in patients with HBV DNA in sera were 43%, 57%, 57%, 57% and 57% at the end of 1st, 2nd, 3rd, 4th and 5th year after normalization of ALT, respectively, and those in patients without demonstrable HBV DNA were 50%, 66%, 74%, 74% and 83%, respectively; thus, the difference in the cumulative reactivation rates between patients with and without serum HBV DNA was not statistically significant (p = 0.79), and irrespective of the status of HBV DNA in sera by PCR, reactivations occurred very rarely after 2 years of a sustained remission. Conclusions We conclude that the seroconversion to anti-HBe accompanied by disappearance of serum HBV DNA even by PCR does not necessarily suggest a sustained remission of chronic hepatitis B.

OBJECTIVES There are regions in the core gene of hepatitis B virus (HBV) where missense mutations are clustered, and mutations in that region are related to severe liver disease. However, there were some differences of the major regions for mutation clustering among ethnic groups. To explore the phenomenon of clustering mutations in Korean patients with chronic HBV infection and to elucidate the correlation between clustering mutation region of the core gene and the severity of liver damage, we analyzed the precore/core gene sequence of HBV in the sera from fifteen chronic hepatitis B (CH-B) patients. METHODS We analysed the HBV precore and core sequences in the sera obtained from fifteen patients (14 males and 1 female, mean age 30.0 years) with biopsy-proven CH-B. The patients were divided into two groups according to the pathological severity of CH-B; namely, group I consisted of 8 patients with chronic persistent hepatitis (CPH), and group II included 7 patients with chronic active hepatitis (CAH). After extraction of HBV DNA from each serum by proteinase K and phenol-chloroform solution, the entire precore and core region of HBV was amplified by PCR, and then the PCR products were subjected to direct sequencing using thermostable DNA polymerase. Fisher's exact test and Mann-Whitney U test were used for statistical analysis. RESULTS A total of 181 nucleotide substitutions were found in the HBV core gene from the 15 CH-B patients, of which 23 were missense and 158 were silent. The nucleotide and amino acid substitution rates were not significantly different between the two groups (p > 0.05). Two mutational hot spots (MHS), codons 21-34 (MHS1) and codons 85-100 (MHS2), were found in the deduced amino acid alignment of the core gene. The alteration rate of amino acid residue in these regions were 2.857 x 10(-2) and 5.000 x 10(-2), respectively. Of 8 CPH patients, 5 showed missense mutations only in MHS2. In comparison, of 7 CAH patients, 3 showed them both in MHS1 and MHS2, 1 only in MHS1, and 1 only in MHS2; thus, missense mutation in MHS1 was exclusively found in patient with CAH. CONCLUSIONS There were two mutation clusterings in the core region of adr subtype of HBV from Korean CH-B patients. Mutations in MHS1 (codon 21-34), but not in MHS2 (codon 85-100), are more likely to be related to the severity of CH-B. A longitudinal study using sequential samples is warranted to further clarify the role of MHS1 in the pathogenesis of more severe CH-B.

Most bronchogenic cysts occur in the mediastinum. However, they may be found near any organ derived from the embryonic foregut, even in the extrathoracic region. We report a case of subphrenic bronchogenic cyst that was initially confused with a solid lesion because of its unusual location and atypical appearance on ultrasonography, computed tomography, and magnetic resonance imaging.

Backgrounds & aims Intrahepatic recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) occurs as a result of direct dissemination or de novo oncogenesis. Hepatocellular carcinogenesis is related to the progression of cirrhosis, and noninvasive fibrosis scoring systems reflect the severity of hepatic fibrosis. Hence, the aim of this study was to elucidate the correlation between noninvasive fibrosis indices and intrahepatic distant recurrence (IDR) of HCC after RFA. Methods Patients with hepatitis B virus (HBV)-related, solitary HCC undergoing RFA were prospectively enrolled. Noninvasive serum fibrosis indices were calculated at the time of RFA. IDR was defined as recurrent HCC beyond >2 cm from the ablation margin of RFA. Predictors of IDR and overall survival were analysed by a Cox regression model. Results Two hundred forty-six patients received RFA as initial treatment, and the median follow-up duration was 19.7 months (IQR, 11.9–29.8). Among these cases, 133 (45.9%) showed IDR after RFA. In multivariable analysis, serum alpha-fetoprotein (AFP) (HR, 1.000; 95% CI, 1.000–1.001; P = 0.001) and age-platelet index (API) (1.19; 1.01–1.39; P = 0.033) were independent predictors of IDR. In particular, patients with API ≤7 showed a significantly higher recurrence-free survival rate than patients with API >7 (P = 0.004). With regard to overall survival, male sex (4.69; 1.52–14.52; P = 0.007), serum bilirubin (2.78; 1.31–5.90; P = 0.008) and AFP (1.000; 1.000–1.001; P = 0.006) were significantly correlated with shortened survival. Conclusion High levels of AFP and API predict IDR of HBV-related HCC after RFA. Therefore, noninvasive fibrosis indices could play an important role in predicting IDR of HCC following percutaneous ablation.

Although lamivudine (LAM) prophylaxis is recommended for patients infected with hepatitis B virus (HBV) undergoing chemotherapy for malignant disease, HBV reactivation sometimes occurs during or after LAM administration. The aim of this study was to determine predictors of LAM prophylactic failure in patients with malignancies. Patients with malignancies were routinely screened for serum hepatitis B surface antigen (HBsAg) from June 2002 to August 2008. All consecutive, HBsAg-positive patients received LAM prophylaxis during and after completion of chemotherapy. We assessed risk factors for virologic breakthrough and withdrawal hepatitis. Death without HBV reactivation was regarded as a competing risk event, which was adjusted by Fine and Gray's model. A total of 110 patients were included in this study. They received LAM prophylaxis for a median of 9.2 months. Virologic breakthrough occurred in 15 patients at a median of 10.9 months from the initiation of LAM prophylaxis. Withdrawal hepatitis occurred in 15 patients at a median of 2.4 months after cessation of LAM prophylaxis. Multivariable analysis showed that high baseline HBV DNA titer (≥2,000 IU/ml) (hazard ratio [HR], 9.94; P = 0.0063) and the use of rituximab (HR, 3.19; P = 0.027) were significant predictors of virologic breakthrough and that high baseline HBV DNA titer (HR, 5.90; P = 0.007), liver cirrhosis (HR, 10.4; P = 0.002), and distant metastasis (HR, 5.14; P = 0.008) were independent risk factors for withdrawal hepatitis. Patients with high viremia, liver cirrhosis, rituximab treatment, and distant metastasis are at high risk of prophylactic failure and need antiviral agents with a greater barrier to resistance.

Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)-measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0

Polymorphisms near the IL28B gene have been proposed to be strongly associated with treatment response and the rate of spontaneous clearance of hepatitis C virus infection, and treatment response of hepatitis B virus (HBV) infection. In this study, we aimed to determine whether these polymorphisms could affect natural courses of HBV infection.Genetic variations were identified through direct DNA sequencing using TaqMan assay in 1,439 patients with past or present HBV infection. Subjects included 404 spontaneously recovered patients, 313 chronic hepatitis B (CHB) patients, 305 liver cirrhosis (LC) patients and 417 hepatocellular carcinoma (HCC) patients. Three polymorphisms near the IL28B gene, rs8099917TG, rs12979860CT and rs12980275AG, were identified. Associations between these polymorphisms and HBV clearance, hepatitis B e antigen (HBeAg) clearance as well as HCC occurrence among patients were analyzed using logistic regression analyses adjusted for age and gender.There were no significant associations between these polymorphisms and the HBV clearance both in CHB and LC groups. Similarly, these polymorphisms showed no significant associations with HBeAg clearance and the occurrence of HCC either.No significant association was identified between polymorphisms near the IL28B gene and the natural courses of chronic HBV infection, including the HBV clearance and HCC occurrence.

Background: Micro RNAs-371-372-373 (miRNAs-371-373), originating from the same pri-miRNA transcript, are reported to be upregulated in hepatocellular carcinoma (HCC) and to be related to the regulation of hepatitis B virus (HBV) infection. Our study investigated whether pri-miRNAs-371-373 polymorphisms are associated with the risk of HCC occurrence and HBV clearance. Methods: Genetic variations were identified through direct DNA sequencing using TaqMan assay. Three sequence variants of pri-miRNAs-371-373 were identified. Genetic associations of those with HCC occurrence and HBV clearance among patients with HBV infection were analyzed using logistic regression analyses with adjustment for age and gender (n = 1439). Results: For the occurrence of HCC, polymorphism rs3859501C > A acted as a protective factor both in chronic carriers (OR = 0.75, P = 0.005 in a codominant model; OR = 0.71, P = 0.02 in a dominant model; OR = 0.66, P = 0.03 in recessive model) and liver cirrhosis patients (OR = 0.69, P = 0.001 in a codominant model; OR = 0.60, P = 0.003 in a dominant model; OR = 0.63, P = 0.03 in a recessive model). The pri-miRNAs-371-373_ht2 [C-A-C] also showed a protective effect on HCC occurrence both in the chronic carrier and liver cirrhosis groups (P < 0.05 in both). However, there was no significant association between pri-miRNAs-371-373 polymorphisms and HBV clearance. Conclusions: In conclusion, among chronic carriers and liver cirrhosis patients, the A allele of rs3859501 and the haplotype pri-miRNAs-371-373_ht2 were more protective to HCC than other genotypes and haplotypes. Further studies into the roles of rs3859501 and pri-miRNAs-371-373_ht2 haplotype in hepatocarcinogenesis are needed.