Su Jong Yu

A genome-wide association study identified new variants associated with the risk of chronic hepatitis B

UNLABELLED Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, several genome-wide association studies (GWASs) of CHB identified human leukocyte antigen (HLA) loci, including HLA-DP and HLA-DQ in Asian populations, as being associated with the risk of CHB. To confirm and identify the host genetic factors related to CHB infection, we performed another GWAS using a higher-density chip in Korean CHB carriers. We analyzed 1400 samples from Korean population (400 CHB cases and 1000 population controls) using a higher-density GWAS chip [1 140 419 single nucleotide polymorphisms (SNPs)]. In subsequent replication analysis, we further analyzed in an independent study of a Korean CHB cohort consisting of 2909 Korean samples (971 cases and 1938 controls). Logistic regression methods were used for statistical analysis adjusting for age and sex as covariates. This study identified two new risk-associated loci for CHB on the HLA region of chromosome 6, e.g. rs652888 on euchromatic histone-lysine-methyltransferase 2 (EHMT2, P = 7.07 × 10(-13)) and rs1419881 on transcription factor 19 (TCF19, P = 1.26 × 10(-18)). Conditional analysis with nearby HLA CHB loci that were previously known, confirmed the independent genetic effects of these two loci on CHB. CONCLUSION The GWAS and the subsequent validation study identified new variants associated with the risk of CHB. These findings may advance the understanding of genetic susceptibility to CHB.

Long-term prognosis of combined hepatocellular and cholangiocarcinoma after curative resection comparison with hepatocellular carcinoma and cholangiocarcinoma.

Goal In this study, we attempted to evaluate the prognosis of combined hepatocellular and cholangiocarcinoma (cHCC-CC) with comparison to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CC). Background The prognosis of cHCC-CC has not been fully elucidated. In this study, we attempted to evaluate the prognosis of cHCC-CC with comparison to HCC and CC. Study Consecutive patients who underwent curative resection for cHCC-CC at a single tertiary care center in Korea and their age, sex, and Child-Turcotte-Pugh class matched HCC and CC patients were included. We evaluated time-to-recurrence (TTR) and overall survival (OS) of cHCC-CC cases and compared them with HCC and CC patients. Results Thirty cHCC-CC, 60 HCC, and 60 CC patients were included. For cHCC-CC group, the median TTR and OS were 5.4 and 18.0 months. After adjustment for confounding factors, the cHCC-CC group had a shorter TTR than did HCC group [relative risk (RR), 2.76; P<0.001] and CC group (RR, 2.00; P=0.013), and a shorter OS than HCC group (RR, 4.70; P<0.001). Compared with the each stage I diseases, cHCC-CC had shorter TTR than HCC (RR, 4.59; P=0.001) and CC (RR, 2.74, P=0.015) and shorter OS than HCC (RR, 9.35; P=0.001). Conclusions The results of this study indicated that cHCC-CC had a significantly poorer prognosis than HCC and CC even after curative resection.

Small Single-Nodule Hepatocellular Carcinoma: Comparison of Transarterial Chemoembolization, Radiofrequency Ablation, and Hepatic Resection by Using Inverse Probability Weighting

PURPOSE To compare the effectiveness of transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and hepatic resection (HR) in patients with small single-nodule hepatocellular carcinoma by using inverse probability weighting to control selection bias. MATERIALS AND METHODS This retrospective cohort study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The study included 197 consecutive patients (146 men and 51 women; mean age ± standard deviation, 57.4 years ± 9.7) with single-nodule hepatocellular carcinomas measuring 3 cm or smaller and no vascular invasion who were treated initially with HR (n = 52), RFA (n = 79), or TACE (n = 66) from January 2005 to December 2006 at a single tertiary hospital. The primary endpoint was overall survival. RESULTS The baseline liver status of the groups differed significantly and was most favorable for the HR group, followed by the RFA group, and then the TACE group. The 5-year overall survival rates were 93.6% in the HR group, 86.6% in the RFA group, and 74.2% in the TACE group (P = .023). However, after inverse probability weighting, weighted survival rates among the three groups were similar (5-year overall survival: 85.6% with HR, 87.6% with RFA, and 80.7% with TACE; P = .834). In multivariate Cox regression analysis, TACE showed a hazard ratio of 0.978 (95% confidence interval: 0.407, 2.347; P = .960) compared with HR and of 1.335 (95% confidence interval: 0.619, 2.879; P = .461) compared with RFA. CONCLUSION TACE is an effective treatment that allows achievement of long-term survival rates comparable to those with HR and RFA in patients with small single-nodule hepatocellular carcinoma.

High liver fibrosis index FIB‐4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers

Screening for hepatocellular carcinoma (HCC) is clinically important given that its early detection has remarkable survival benefits. We investigated the possible role of FIB‐4, a recently developed noninvasive marker for liver fibrosis based on routine laboratory tests, as a clinical indicator for predicting future HCC among hepatitis B surface antigen (HBsAg) carriers. Our retrospective cohort study involved 986 Korean HBsAg carriers 40 years of age or older who visited Seoul National University Hospital for a health checkup. National medical service claims data were used to determine HCC incidence. Median follow‐up time was 5.4 years (interquartile range: 4.4 years). Adjusted for age, sex, body mass index, smoking, alcohol, and antiviral medication for hepatitis B, compared to subjects with FIB‐4 <1.25, subjects with 1.7≤ FIB‐4 <2.4 showed an adjusted hazard ratio (aHR) of 4.57 (95% confidence interval [CI]: 1.50‐13.92) and subjects with FIB‐4 ≥2.4 showed an aHR of 21.34 (95% CI: 7.73‐58.92) for HCC incidence. FIB‐4 was shown to have incremental predictive value to ultrasonographic liver cirrhosis for HCC incidence (C‐index: 0.701 vs. 0.831; P = 0.001). FIB‐4 was also better predictive of HCC incidence, compared to that of ultrasonographic liver cirrhosis (C‐index: 0.775 vs. 0.701; P = 0.040). Conclusion: High FIB‐4 is a highly predictive risk factor for HCC incidence among Korean HBsAg carriers. FIB‐4 is a promising, easily applicable, and cost‐effective clinical tool in identifying a subpopulation of HBsAg carriers who are at heightened risk. Our study needs to be replicated in larger future studies on various ethnic groups; nonetheless, our study suggests that FIB‐4 may play a valuable role in HCC screening among HBsAg carriers. (Hepatology 2015;61:1261–1268)

Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition

Abstract3-bromopyruvate (3-BP), a hexokinase (HK) II inhibitor, promotes tumor cell death by inducing endoplasmic reticulum (ER) stress in human hepatocellular carcinoma (HCC) cell lines. Protein disulfide isomerase (PDI) is an essential folding catalyst and attenuates ER stress by folding the misfolded proteins. We examined if PDI is expressed in hypoxic HCC cells, and evaluated its inhibition potentiated HK II inhibitor-induced ER stress in hypoxic HCC cells. HCC apoptotic cell death was assessed by DAPI staining and apoptotic signaling pathways were explored by immunoblot analysis. An in vivo model of HCC was established in C3H mice intradermally with implanted MH134 cells. 3-BP with/without a PDI inhibitor (bacitracin) was subsequently administered. The anti-tumor efficacies were evaluated by measuring tumor volumes and quantifying apoptotic cells and microvessel densities (MVDs). HCC cells were found to express PDI in a hypoxia-inducible manner. The simultaneous treatment of bacitracin and 3-BP enhanced 3-BP-induced apoptosis. This enhancement was attributed to increased ER stress and JNK activation compared to the cells treated with just 3-BP. In an in vivo model of HCC, tumor growth was significantly suppressed in mice co-treated with bacitracin and 3-BP, and the percentages of apoptotic cells significantly increased and MVDs significantly decreased. These results demonstrated that PDI was induced in hypoxic HCC tissue and that PDI inhibition enhanced HK II inhibitor-induced anti-tumor efficacy synergistically via augmenting ER stress and anti-angiogenesis in vivo. Thus, blockage of PDI activity in combination with HK II inhibitor may be therapeutically useful in HCCs.

Non-hypervascular hepatobiliary phase hypointense nodules on gadoxetic acid-enhanced MRI: Risk of HCC recurrence after radiofrequency ablation

BACKGROUND & AIMS Hepatobiliary phase images (HBPI) of gadoxetic acid-enhanced MRI can depict borderline hepatocellular nodules that have the potential to progress into hypervascular hepatocellular carcinomas (HCCs), as non-hypervascular hypointense nodules. We retrospectively evaluated the impact of the presence of non-hypervascular hypointense nodules at HBPI of gadoxetic acid-enhanced MRI on the patients prognosis after radiofrequency ablation (RFA) for early stage HCCs. METHODS A total of 139 patients who underwent pre-procedural gadoxetic acid-enhanced MRI followed by RFA were included. After a mean follow-up of 44.6±13.2 months, we compared the results of tumor recurrence as well as overall and recurrence-free survival (RFS) with the presence of non-hypervascular hypointense nodules on HBPI. RESULTS The presence of non-hypervascular hypointense nodules on HBPI did not affect overall survival (p=0.136). However, the estimated 5-year RFS rate was 71.3% in 29 patients without non-hypervascular hypointense nodules on HBPI compared to 27.9% in 110 patients with non-hypervascular hypointense nodules on HBPI, indicating a significant difference (hazard ratio=2.84 [1.39-5.98], p=0.006). When we classified recurrence into local tumor progression [LTP], intrahepatic distant recurrence [IDR], and extra-hepatic metastasis [EM], five-year cumulative incidences (CI) of IDR in patients with non-hypervascular hypointense nodules on HBPI were significantly higher than those in patients without non-hypervascular hypointense nodules on HBPI (17.9% vs. 67.5%, p<0.001). Five-year CIs of LTP and EM showed no significant difference (p>0.05). CONCLUSIONS The presence of non-hypervascular hypointense hepatocellular nodules on HBPI of gadoxetic acid-enhanced MRI taken prior to RFA is a significant predictive factor of recurrence after RFA of early stage HCCs, particularly IDR.

Hypoxia and retinoic acid-inducible NDRG1 expression is responsible for doxorubicin and retinoic acid resistance in hepatocellular carcinoma cells.

Hypoxia may activate survival signals in cancer cells. Moreover, hypoxic cells are less sensitive than normoxic cells to doxorubicin cytotoxicity, a potent activator of the p53 tumor suppressor gene. N-myc downstream-regulated gene-1 (NDRG1) is a hypoxia- and retinoic acid-inducible protein, and has been previously implicated in carcinogenesis. As this protein is also a downstream target of p53 and hepatocellular carcinoma (HCC) cells frequently evidence resistance to retinoic acid (RA) cytotoxicity, we attempted to determine whether the suppression of NDRG1 expression may sensitize HCC cells to doxorubicin and/or RA cytotoxicity. HCC cells expressed NDRG1 protein, and the expression of this protein was hypoxia- and RA-inducible. Doxorubicin treatment induced HCC cell cytotoxicity via the activation of mitochondrial apoptotic signals, including caspase-9 activation. Hypoxic HCC cells are less sensitive to doxorubicin-induced apoptosis. The suppression of NDRG1 expression either by siRNA or flavopiridol sensitized hypoxic HCC cells to doxorubicin cytotoxicity, and this was attributed to more profound augmentation of JNK and caspase-9 activation. The suppression of NDRG1 expression also sensitized RA-resistant HCC cells to RA-induced apoptosis, and this sensitization was more apparent in hypoxic HCC cells than in normoxic cells. Glutaredoxin2 expression was down-regulated in NDRG1-suppressed HCC cells. These results show that hypoxia- and RA-inducible NDRG1 expression is responsible for doxorubicin and RA resistance in HCC cells. Thus, the selective interruption of NDRG1 signaling may prove to be therapeutically useful in HCCs, particularly in the advanced infiltrative type of tumors exposed to hypoxic environments.

CLIF-SOFA scoring system accurately predicts short-term mortality in acutely decompensated patients with alcoholic cirrhosis: a retrospective analysis

Accurate prognostication of acute‐on‐chronic liver failure (ACLF) is essential for therapeutic decisions. Our aim was to validate a novel scoring system for predicting mortality, the chronic liver failure‐sequential organ failure assessment (CLIF‐SOFA), in a population of Asian patients with ACLF.

Visceral Obesity Predicts Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

AbstractNonalcoholic fatty liver disease (NAFLD) is associated with visceral obesity. However, the association between visceral adipose tissue (VAT) area and fibrosis in NAFLD patients has not been completely established. This study was aimed to determine the relationship between the computed tomography-measured VAT area and significant fibrosis in NAFLD patients. A total of 324 NAFLD patients and 132 controls were evaluated by liver biopsy. NAFLD was diagnosed based on histological examinations and alcohol consumption <20 g/day. The NAFLD patients showed a higher age and gender-adjusted VAT area than the control group (86.1 ± 2.3 vs 56.7 ± 3.7, P < 0.001). The VAT area increased across the control, NAFLD without significant fibrosis, and NAFLD with significant fibrosis groups (54.9 ± 3.5, 80.6 ± 2.4, and 123.4 ± 6.4, P < 0.001). This association persisted after adjusting for multiple confounders (P for trend = 0.028). A multivariate regression analysis demonstrated the VAT area was independently associated with NAFLD with significant fibrosis (F2–F4) (odds ratio [OR] 1.21 95% confidence interval [CI] 1.07–1.37 per 10 cm2 increase of VAT area; OR 2.62 [per 1 – standard deviation (SD)] 95% CI 1.41–4.86). Moreover, a multivariate logistic regression analysis revealed the VAT area was independently associated with nonalcoholic steatohepatitis (NASH) in NAFLD (OR 1.17 95% CI 1.05–1.32 per 10 cm2 increase of VAT area; OR 2.21 [per 1 – SD] 95% CI 1.25–3.89). Increased VAT area is independently associated with NASH or significant fibrosis and VAT might be a central target for lifestyle modifications in NAFLD patients.

Efficacy of Entecavir-Tenofovir Combination Therapy for Chronic Hepatitis B Patients with Multidrug-Resistant Strains

ABSTRACT 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 and P = 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.