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We investigated whether liver stiffness (LS) values can predict liver-related events (LREs) development in patients with chronic hepatitis B (CHB).LS values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease.Between June 2007 and May 2010, a total of 162 patients with CHB who completed 2-year entecavir (ETV) treatment were evaluated. The primary endpoint was LRE development (hepatic decompensation, hepatocellular carcinoma, or liver-related death) during the 2-year ETV treatment.The median age of the patients (99 men, 63 women) was 51 years, and the median LS value was 14.8 kPa. During the 2-year ETV treatment, 15 (9.3%) patients experienced LREs. On univariate analysis, age, the proportion of patients with liver cirrhosis, platelet counts, and baseline LS values were significantly associated with LRE development (all P0.05). Together with age, multivariate analysis identified baseline LS values as an independent predictor of LRE development (P=0.046; hazard ratio, 1.040; 95% confidence interval, 1.101-1.084). The cutoff LS value maximizing the sum of sensitivity and specificity was 12.0 kPa (area under the receiver operating characteristics curve, 0.736; P=0.003; sensitivity, 93.3%; specificity, 42.2%). In addition, the changes in LS values between baseline and 1-year ETV treatment showed significant correlations with LRE development (P=0.030).Our data suggest that LS values are predictive of LRE development during 2-year ETV treatment in patients with CHB. The potential role of LS value as a monitoring tool for predicting dynamic changes in the risk of LRE development during long-term ETV treatment should be investigated further.

To compare hepatocellular carcinoma (HCC) stage, treatment modality, and survival between groups submitted to different surveillance interval.It is not clear if surveillance interval affects patient survival with HCC.Clinical data from 10,307 patients at risk for HCC were prospectively collected from 1990 to 2005. The characteristics of cancer and 5-year survival in patients diagnosed as HCC during follow-up were compared between surveillance interval of6 months and beyond 6 months.A total of 400 patients were diagnosed with HCC, with a mean tumor size of 3.5 cm and an annual detection rate of 2.4%. The tumor sizes detected in patients with surveillance interval ≤ 6 months were significantly smaller than those detected in patients with interval of6 months (n=219; 3.0 ± 1.7 cm vs. n=181; 4.0 ± 2.6 cm, P0.001). The survival benefit in patients with surveillance interval of ≤ 6 months was significant compared with those with interval of6 months even after considering lead time with assumed tumor doubling time of 60 days. The 5-year survival of HCC patients surveyed between 2000 and 2004 was significantly higher compared with those surveyed between 1990 and 1994 or between 1995 and 1999 (41% vs. 17% and 19%, respectively, P0.0001). Using a Cox regression model, Child-Pugh class, Japanese tumor-node-metastasis stage, and α-fetoprotein levels were independently associated with patient survival.Our data show that surveillance ≤ 6 months might be associated with early detection of HCC and improved survival in a hepatitis B endemic area.

BACKGROUND/AIMS Liver stiffness measurement (LSM) using transient elastography (FibroScan) is influenced by major changes in aminotransferase. We aimed to determine the optimal time for restoring the reliability of LSM for assessing liver fibrosis in patients with chronic hepatitis B experiencing acute exacerbation. METHODS Twenty-one patients with acute exacerbation of chronic hepatitis B [alanine aminotransferase (ALT)>5× upper limit of normal (ULN)] were prospectively recruited. Serial LSM and biochemical tests were performed at the time of admission and after 1, 3, 6, 9, and 12 months. The ULN of ALT was defined as 40 IU/L. The cutoff LSM value for cirrhosis was defined as 10.3 kPa. RESULTS The median age (9 male) was 49 years. The median ALT and LSM in the baseline were 522 IU/L and 15.1 kPa, respectively. Three months after acute exacerbation, ALT had decreased significantly below 2× ULN and stabilized (median: 522, 43, 21, 19, 18, and 16 IU/L at baseline, 1, 3, 6, 9, and 12 mo, respectively). However, LSM needed 3 more months (6 mo after exacerbation) for stabilization (median: 15.1, 10.0, 7.4, 7.1, 6.3, and 5.8 kPa at baseline, 1, 3, 6, 9, and 12 mo, respectively). CONCLUSIONS LSM should be postponed for at least 3 months after stabilization of ALT below 2× ULN to restore the reliability of LSM in assessing liver fibrosis.

Liver stiffness measurement (LSM) using transient elastography (FibroScan) can accurately assess the degree of liver fibrosis and predict the development of hepatocellular carcinoma (HCC) and variceal bleeding in patients with chronic hepatitis B (CHB).We compared the accuracy of noninvasive liver fibrosis prediction methods in predicting the development of HCC or hepatic decompensation in patients with CHB.A total of 1126 patients with CHB who underwent LSMs and attended regular follow-ups to detect the development of HCC and hepatic decompensations (variceal bleeding, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatorenal syndrome) were enrolled. Noninvasive liver fibrosis prediction methods included, age-spleen-to-platelet ratio index, LSM, LSM-spleen diameter-to-platelet ratio index (LSPI), P2/MS, and FIB-4.During follow-up (median, 30.7 mo), HCC and hepatic decompensation developed in 63 and 68 patients, respectively. The accuracy of LSM and LSPI in predicting the development of HCC or hepatic decompensation was higher than that of aspartate aminotransferase-to-platelet ratio index, age-spleen-to-platelet ratio index, P2/MS, or FIB-4 (areas under the receiver operating characteristic curve=0.789 and 0.788 vs. 0.729, 0.756, 0.696, and 0.744 for HCC development; areas under the receiver operating characteristic curve=0.820 and 0.848 vs. 0.787, 0.799, 0.812, and 0.784 for hepatic decompensation). On multivariate analyses, LSM and LSPI were identified as independent predictors of the development of HCC [hazard ratio (HR), 1.040 (LSM); HR, 1.001 (LSPI)] and hepatic decompensation [HR, 1.033 (LSM); HR, 1.002 (LSPI)].Our results suggest that LSM or LSPI may be useful predictors of the development of HCC and hepatic decompensation in patients with CHB.

Risk Assessment of Esophageal Variceal Bleeding in B-Viral Liver Cirrhosis by a Liver Stiffness Measurement-Based Model

Quantitative hepatitis B surface antigen (qHBsAg) and quantitative hepatitis B e antigen (qHBeAg) titers are emerging as useful tools for measuring viral loads and for predicting the virological response (VR) and serological response (SR) to pegylated interferon therapy. However, the clinical utility of these assays in patients taking entecavir (ETV) is largely unknown. Treatment-naive patients with chronic hepatitis B (CHB) who were taking ETV for 2 years were enrolled. The qHBsAg and qHBeAg levels were serially measured with the Architect assay. From 95 patients, 60.0% of whom were hepatitis B e antigen–positive [HBeAg(+)], 475 samples were analyzed. The median baseline log hepatitis B virus (HBV) DNA, log qHBsAg, and log qHBeAg values were 6.73 copies/mL (4.04-9.11 copies/mL), 3.58 IU/mL (1.17-5.10 IU/mL), and 1.71 Paul Ehrlich (PE) IU/mL (−0.64 to 2.63 PE IU/mL), respectively. For the prediction of VR (HBV DNA < 60 copies/mL at 24 months) in HBeAg(+) patients, baseline alanine aminotransferase (P = 0.013), HBV DNA (P = 0.040), and qHBsAg levels (P = 0.033) were significant. For the prediction of VR, the area under the curve for the baseline log qHBsAg level was 0.823 (P < 0.001); a cutoff level of 3.98 IU/mL (9550 IU/mL on a nonlogarithmic scale) yielded the highest predictive value with a sensitivity of 86.8% and a specificity of 78.9%. As for SR (HBeAg loss at 24 months), the reduction of qHBeAg was significantly greater in the SR(+) group versus the SR(−) group. The sensitivity and specificity were 75.0% and 89.8%, respectively, with a decline of 1.00 PE IU/mL at 6 months. With ETV therapy, the correlation between HBV DNA and qHBsAg peaked at 6 months in HBeAg(+) patients. Conclusion: Both qHBsAg and qHBeAg decreased significantly with ETV therapy. The baseline qHBsAg levels and the on-treatment decline of qHBeAg in HBeAg(+) patients were proven to be highly useful in predicting VR and SR, respectively. The determination of qHBsAg and qHBeAg can help us to select the appropriate strategy for the management of patients with CHB. However, the dynamic interplay between qHBsAg, qHBeAg, and HBV DNA during antiviral therapy remains to be elucidated. (Hepatology 2011;)

Periodic endoscopic screening for esophageal varices (EVs) and prophylactic treatment for high-risk EVs ((HEVs); (1) medium/large EVs and (2) small EVs with red sign or decompensated cirrhosis) are currently recommended for all cirrhotic patients. However, if a simple, noninvasive test is available, many low-risk patients may safely avoid endoscopy. We developed and validated a new liver stiffness measurement (LSM)-based prediction model for HEVs.We prospectively enrolled 280 consecutive B-viral cirrhosis patients from 2005 to 2007 (training set) and 121 from 2007 to 2008 (validation set). All underwent laboratory workups, endoscopy, LSM, and ultrasonography. For detection of HEVs, univariate and multivariate analysis were performed, using chi2-test/t-test and logistic regression, respectively. A prediction model was derived from multivariate predictors.In the training set, 90 had HEVs, and multivariate analysis showed significant differences in LSM, spleen diameter, and platelet count between patients with and without HEVs. We developed LSM-spleen diameter to platelet ratio score (LSPS): LSM x spleen diameter/platelet count. The area under the receiver-operating characteristic curve (AUROC) in the training set was 0.954. At LSPS3.5, 94.0% negative predictive value (NPV) was provided (184 patients), whereas 94.2% positive predictive value (PPV) was achieved (69 patients) at LSPS5.5. Overall, the likelihood of HEVs was correctly diagnosed in 253 patients (90.3%). Its predictive values were maintained at similar accuracy in subsequent validation set (AUROC=0.953; 94.7% NPV/93.3% PPV at cutoff 3.5/5.5, respectively).LSPS is a reliable, noninvasive method for detection of HEVs. Patients with LSPS3.5 may avoid endoscopy safely, whereas those with LSPS5.5 should be considered for appropriate prophylactic treatments.

To evaluate the efficacy and safety of transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (HCC) after curative resection and to examine the factors associated with the prognosis in a single center.Between January 1995 and July 2006, 169 patients who had undergone curative resection were diagnosed with recurrent HCC. Of these, 114 patients underwent TACE as first-line therapy and were followed until July 2007.At the time of resection, the mean tumor size was 4.8 + or - 2.9 cm, and 96 (84.2%) patients had a single tumor. Single nodular recurrence was observed in 53 (46.5%) patients. The mean size of the recurrent HCC was 2.1 + or - 1.2 cm. The disease-free survival after TACE was 46.0%, 16.7%, and 13.4% at 1, 2, and 3 years, respectively. The overall survival after TACE was 77.8%, 53.6%, and 31.6% at 1, 3, and 5 years, respectively. Cox regression analysis revealed that the Edmonson grade and time to recurrence (6 months) independently affected the disease-free survival (both P0.05). The time to recurrence (6 months) and tumor-node-metastasis stage were associated with overall survival (both P0.05). Only 1 lethal complication (biliary sepsis) occurred after TACE.TACE seems to be a safe, effective treatment for recurrent HCC after curative resection.

Goals: We aimed to determine whether the presence of large liver cell dysplasia (LLCD) and/or small LCD (SLCD) in chronic hepatitis B is a risk factor for hepatocellular carcinoma (HCC) development. Background: A close relationship between LLCD/SLCD and hepatitis B virus has been observed and SLCD has been proposed to be a putative precursor of HCC, whereas the significance of LLCD is still controversial. Study: One hundred eighty-one patients with chronic hepatitis B who underwent needle liver biopsy were evaluated for the presence of LLCD/SLCD. The predictive value of LLCD/SLCD for HCC development was assessed. Results: LLCD and SLCD were present at initial biopsy in 82 (45%) and 17 (9%) patients, respectively. During the mean follow-up of 115 ± 48 months, 19 (10%) cases were diagnosed of HCC, of which 13 (76%) and 3 (17%) cases had demonstrated LLCD and SLCD, respectively, at initial evaluation. The patients with LLCD showed a significantly higher cumulative probability of HCC development than those without LLCD (P=0.016). The risk of HCC development in the presence of LLCD was approximately 3-fold, with positive and negative predictive values of 15.9% and 94.9%, respectively. The patients with SLCD showed no significant difference in cumulative probability of HCC development compared with those without (P> 0.05). Conclusions: LLCD in chronic hepatitis B is considered to be one of the risk factors for HCC development and its presence may help to identify a high-risk subgroup of patients requiring more intensive screening for HCC.

It is generally recommended that patients with chronic viral hepatitis should be vaccinated against hepatitis A virus (HAV) infection. We intended to evaluate the prevalence of IgG anti-HAV according to age in patients chronically infected with hepatitis B virus or hepatitis C virus in Korea.From June to October 2006, 303 patients (226 male, 77 female) with chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma were recruited (mean age 50.8+/-14.4 years; range 16-84). The sera were tested for antibodies to HAV, and overall and age-specific seroprevalence of anti-HAV was assessed.Hepatitis B virus infection was the etiology of liver diseases in 267 patients (88.1%), with hepatitis C virus infection in 36 (11.9%). The distribution of clinical diagnosis was chronic hepatitis in 86 patients (28.4%), liver cirrhosis in 36 (11.9%), and hepatocellular carcinoma in 181 (57.9%). The patients were categorized by decade of age and the distribution was as follows: nine patients (2.5%) in their teens, 23 (6.2%) in their 20s, 36 (12.4%) in their 30s, 78 (25.7%) in their 40s, 72 (24.1%) in their 50s, and 85 (29%)or=61 years. The overall seroprevalence of anti-HAV was 87.8% (266/303), and no difference was observed in sex (86.7 vs. 90.9%, P=0.42). The seroprevalence in each age group was 22.2, 26.1, 72.2, 97.4, 100 and 98.8%, respectively, showing marked increase in those over 40 years of age (P0.001).Our study demonstrates that most Korean patients over 40 years of age with chronic liver disease have already been exposed to HAV.

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Although the mechanism of susceptibility to chronic persistent hepatitis B virus (HBV) infection is not well clarified, immunogenetic factors of the host may have a role. Recently, a strong association between HLA-DR13 and the self-limited course of HBV infection has been reported. To determine whether the elimination of HBV is related to a particular HLA allele, we studied the HBV markers and HLA-DR phenotypes of 1,272 Koreans who had visited Yonsei University Medical Center for renal transplantation. They included 330 renal transplant donors. Subjects were categorized into 3 different groups: the “Unexposed Group” (UE; n = 946) with negative HBV markers, the “Chronic Carrier Group” (CC; n = 83), who were hepatitis B surface antigen (HBsAg)-positive, and the “Spontaneously Cleared Group” (SC; n = 243), who were HBsAg-negative with antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). HLA-DR4 was the most common type in all groups. HLA-DR6 was significantly more frequent in 69 of 243 subjects with SC (28.4%) than in 8 of 83 subjects with CC (9.6%) (P < .001; relative risk [RR] = 3.72). HLA-DR9 was significantly more frequent in CC than in SC (P < .001; RR = 0.33). HLA-DR13 showed a stronger association with the clearance of HBV than the other HLA-DR6 subgroup. The distribution of HLA-DR phenotypes was similar regardless of renal disease. Our data indicate that HLA-DR6, especially HLA-DR13, is one of the host factors, which influences the immune response to HBV, and may be associated with self-elimination of HBV in Koreans.