The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter.

PURPOSE: The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS: Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS: Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. CONCLUSION: Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.

Noninvasive Prediction of Erosive Esophagitis Using a Controlled Attenuation Parameter (CAP)-Based Risk Estimation Model.

BACKGROUND: Erosive esophagitis and fatty liver share obesity and visceral fat as common critical pathogenesis. However, the relationship between the amount of hepatic fat and the severity of erosive esophagitis was not well investigated, and there is no risk estimation model for erosive esophagitis. AIM: To evaluate the relationship between the amount of hepatic fat and the severity of erosive esophagitis and then develop a risk estimation model for erosive esophagitis. METHODS: We enrolled 1045 consecutive participants (training cohort, n = 705; validation cohort, n = 340) who underwent esophagogastroduodenoscopy and CAP. The relationship between severity of fatty liver and erosive esophagitis was investigated, and independent predictors for erosive esophagitis that have been investigated through logistic regression analyses were used as components for establishing a risk estimation model. RESULTS: The prevalence of erosive gastritis was 10.7 %, and the severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation (P < 0.05). A CAP-based risk estimation model for erosive esophagitis using CAP, Body mass index, and significant alcohol Drinking as constituent variables was established and was dubbed the CBD score (AUROC = 0.819, range 0-11). The high-risk group (CBD score ≥3) showed significantly higher risk of having erosive esophagitis than the low-risk group (CBD score <3) (24.1 vs. 2.7 %, respectively; P < 0.001). The diagnostic accuracy of CBD score was maintained in the validation cohort (AUROC = 0.848). CONCLUSION: The severity of erosive esophagitis was positively correlated with the degree of hepatic fatty accumulation, and the CBD score might be a simple CAP-based risk model for predicting erosive esophagitis.

Prognostic indicators for acute liver failure development and mortality in patients with hepatitis A: consecutive case analysis.

PURPOSE: Due to the seroepidemiological shift in hepatitis A (HA), its severity, mortality, and complications have increased in recent years. Thus, the aim of this study was to identify predictive factors associated with poor prognosis among patients with HA. MATERIALS AND METHODS: A total of 304 patients with HA admitted to our institution between July 2009 and June 2011 were enrolled consecutively. Patients with complications defined as acute liver failure (ALF) were evaluated, and mortality was defined as death or liver transplantation. RESULTS: The mean age of patients (204 males, 100 females) was 32 years. Eighteen (5.9%) patients had progressed to ALF. Of the patients with ALF, 10 patients (3.3%) showed spontaneous survival while 8 (2.6%) died or underwent liver transplantation. Multivariate regression analysis showed that Model for End-Stage Liver Disease (MELD) and systemic inflammatory response syndrome (SIRS) scores were significant predictive factors of ALF. Based on receiver operating characteristics (ROC) analysis, a MELD≥23.5 was significantly more predictive than a SIRS score≥3 (area under the ROC: 0.940 vs. 0.742, respectively). In addition, of patients with a MELD score≥23.5, King's College Hospital criteria (KCC) and SIRS scores were predictive factors associated with death/transplantation in multivariate analysis. CONCLUSION: MELD and SIRS scores≥23.5 and ≥3, respectively, appeared to be related to ALF development. In addition, KCC and SIRS scores≥3 were valuable in predicting mortality of patients with a MELD≥23.5.

Dynamics of the liver stiffness value using transient elastography during the perioperative period in patients with valvular heart disease.

BACKGROUND/AIMS: Liver congestion due to heart failure in patients with valvular heart disease (VHD) can result in an overestimate of the liver stiffness (LS) as assessed by transient elastography (TE). This prospective pilot study investigated the dynamics of LS during the perioperative valve operation period. METHODS: Thirty-two patients who underwent a valve operation (case) and 12 who underwent a varicose vein operation (control) were prospectively enrolled. LS and cardiologic parameters at three time points [baseline, post-operative day (POD)7, and POD90] were collected. RESULTS: LS at three time points were consistently higher in the case group than those in the control group, although all participants did not show evidence of underlying chronic liver disease (all P<0.05). In the case group, LS at POD7 increased slightly from the LS at baseline (median 7.9→8.4 kPa, P = 0.816), whereas LS at POD90 decreased significantly from the LS at POD7 (median 8.4→6.0 kPa; P = 0.026). LS was significantly correlated with N-terminal-pro brain natriuretic peptide (NT-proBNP) (ρ = 0.412), left ventricular ejection fraction (ρ = -0.494), and central venous pressure during the operation (ρ = 0.555) at baseline (all P<0.05). LS was significantly correlated with NT-proBNP (ρ = 0.526) and right ventricular pressure (ρ = 0.572) at POD7, whereas LS was significantly correlated with NT-proBNP (ρ = 0.590) at POD90 (all P<0.05). CONCLUSIONS: LS can be overestimated in patients with VHD due to hepatic congestion. However, LS can be dynamically reversed during the perioperative period reflecting the restoration of cardiac function after a successful operation.

Use of the delta neutrophil index as a prognostic factor of mortality in patients with spontaneous bacterial peritonitis: implications of a simple and useful marker.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common and life-threatening infection in patients with advanced cirrhosis. The prognostic value of a novel marker, the delta neutrophil index (DNI), was investigated relative to mortality in patients with SBP. MATERIALS & METHODS: Seventy-five patients with SBP were studied from April 2010 to May 2012. DNI at initial diagnosis of SBP was determined and compared with 30-day mortality rates. RESULTS: Of the patients, 87.7% were men, and the median age of all patients was 59.0 yrs. The area under the receiver-operating characteristic (ROC) curve of DNI for 30-day mortality was 0.701 (95% confidence interval [CI], 0.553-0.849; p = 0.009), which was higher than that of C-reactive protein (0.640, 95% CI, 0.494-0.786; p = 0.076) or the model for end-stage liver disease score (0.592, 95% CI, 0.436-0.748; p = 0.235). From the ROC curve, with the sum of sensitivity and specificity, the cutoff value of DNI was determined to be 5.7%. In the high-DNI group (DNI ≥5.7%), septic shock and 30-day mortality were more prevalent compared with the low-DNI group (84.2% vs. 48.2%, p = 0.007; 57.9% vs. 14.3%, p<0.001, respectively). Patients with an elevated DNI had a higher risk of 30-day mortality compared with those with a low DNI (4.225, 95% CI, 1.631-10.949; p = 0.003). CONCLUSION: A higher DNI at the time of SBP diagnosis is an independent predictor of 30-day mortality in patients with SBP.

Clinical usefulness of double biomarkers AFP and PIVKA-II for subdividing prognostic groups in locally advanced hepatocellular carcinoma.

BACKGROUND & AIMS: In this study, we investigated the clinical usefulness of AFP and PIVKA-II in subdividing prognostic groups in patients with locally advanced HCC treated locally. METHODS: Patients who had undergone local treatment for locally advanced HCC between 2001 and 2006 were enrolled. Response to treatment was defined as a reduction in AFP or PIVKA-II by more than 50% from baseline levels at 1 month after the treatment completion. Patients were divided according to their AFP and PIVKA-II response: A↓P↓ [AFP response (+) and PIVKA-II response (+)]; A↓P↑ [AFP response (+) and PIVKA-II response (-)]; A↑P↓ [AFP response (-) and PIVKA-II response (+)]; A↑P↑ [AFP response (-) and PIVKA-II response (-)]. Clinical characteristics and prognosis were compared between groups. RESULTS: Patients were subdivided into four groups by the change in the level of the biomarkers AFP and PIVKA-II, and the survival outcomes of each group were distinct. Among patients with an AFP response, further subdivision by PIVKA-II response revealed that those in the A↓P↓ group had a longer median progression-free survival (PFS) and overall survival (OS) compared with those in the A↓P↑ group (PFS: 16.2 vs. 5.1 months, P = 0.009; OS: 26.3 vs. 7.3 months, P = 0.017). Combination of AFP and PIVKA-II response showed a predictive power for PFS and OS comparable to radiological criteria and better than AFP response alone. CONCLUSIONS: In patients with locally advanced HCC, the use of a combination of two biomarkers, AFP and PIVKA-II, appears useful in predicting treatment outcomes through the subdivision of prognostic groups.

Risk assessment of liver-related events using transient elastography in patients with chronic hepatitis B receiving entecavir.

GOALS: We investigated whether liver stiffness (LS) values can predict liver-related events (LREs) development in patients with chronic hepatitis B (CHB). BACKGROUND: LS values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease. METHODS: 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. RESULTS: 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 P<0.05). 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). CONCLUSIONS: 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.

Maintaining remission in lamivudine-resistant patients with a virological response to adefovir add-on lamivudine after stopping lamivudine therapy.

BACKGROUND & AIMS: We examined the durability of the virological response after discontinuing lamivudine (LVD) in chronic hepatitis B (CHB) patients with LVD-resistant hepatitis B virus (HBV), who responded to LVD plus adefovir (ADV) combination therapy, and the outcome of switching to ADV monotherapy compared to maintaining combination therapy. METHODS: This study enrolled 72 patients with undetectable viral loads (≤12 IU/ml) and normal alanine aminotransferase levels after ADV add-on therapy for at least 6 months in LVD-resistant CHB patients. The enrolled patients were randomly assigned to continue with LVD-ADV combination therapy or switch to ADV monotherapy (n = 36 per group). Virological rebound was defined as HBV DNA detection at more than 12 IU/ml by quantitative polymerase chain reaction determined on two consecutive measurements. RESULTS: During 96 weeks of follow-up, 100% (36/36) of the patients in the LVD-ADV combination maintained group had persistently undetectable HBV DNA, compared with 94.4% (34/36) patients in the ADV monotherapy switched group. These two patients had undetectable HBV DNA after switching back to LVD-ADV combination therapy. There were no significant differences in the HBsAg levels between the two treatment groups during the 96-week follow-up period. CONCLUSIONS: In our study, switching to ADV monotherapy resulted in sustained HBV DNA suppression in 94.4% of the patients for 96 weeks. Prior complete viral suppression with LVD-ADV combination therapy conferred a significant advantage in patients who switched to ADV monotherapy. LVD may be discontinued in patients who show a complete virological response to LVD-ADV combination therapy for at least 6 months.

Controlled attenuation parameter (CAP) for detection of hepatic steatosis in patients with chronic liver diseases: a prospective study of a native Korean population.

BACKGROUND: Controlled attenuation parameter (CAP) is a non-invasive method of measuring hepatic steatosis using a process based on transient elastography. We investigated the diagnostic accuracy of CAP in detecting hepatic steatosis in patients with chronic liver disease (CLD). METHODS: A total of 135 patients with CLD who underwent liver biopsy and CAP were consecutively enrolled in this prospective study. The performance of CAP for detection of hepatic steatosis compared with liver biopsy was calculated using area under receiver operating characteristics curves (AUROC). Steatosis was categorized into S0 (<5%), S1 (5-33%), S2 (34-66%) and S3 (>66% of hepatocytes). RESULTS: Male gender predominated (n = 87, 64%) and the median age was 51 years. The aetiologies of CLD included non-alcoholic fatty liver disease (n = 56, 41.5%) and chronic viral hepatitis because of hepatitis B (n = 47, 34.8%) and C (n = 12, 8.9%). Steatosis repartition was: S0 31.1% (n = 42), S1 43.7% (n = 59), S2 18.5% (n = 25) and S3 6.7% (n = 9) respectively. In the multivariate analysis, steatosis grade and body mass index were independently associated with CAP (all P < 0.001), whereas fibrosis stage and activity grade were not. The AUROCs of CAP were 0.885 for ≥S1 (sensitivity 73.1%, specificity 95.2%), 0.894 for ≥S2 (sensitivity 82.4%, specificity 86.1%) and 0.800 for S3 (sensitivity 77.8%, specificity 84.1%). The optimal cut-off CAP values that maximized the Youden index were 250 dB/m (≥S1), 299 dB/m (≥S2), and 327 dB/m (=S3) respectively. CONCLUSIONS: Our data showed that CAP had high diagnostic accuracy for detecting hepatic steatosis in patients with CLD and suggested that CAP is also applicable for Asian patients.

Community-acquired vs. nosocomial spontaneous bacterial peritonitis in patients with liver cirrhosis.

BACKGROUND/AIMS: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with end-stage liver disease, but reports comparing community-acquired SBP (CA-SBP) with nosocomial SBP (N-SBP) are rare. This study compared the clinical characteristics, microbiological characteristics, and treatment outcomes of patients with CA-SBP and N-SBP. METHODOLOGY: Records for 248 patients (173 men, 75 women) with cirrhosis who experienced SBP were retrospectively reviewed. RESULTS: The study population included 202 (81.5%) patients with CA-SBP and 46 (18.5%) patients with N-SBP. Patients with CA-SBP or N-SBP showed no significant differences in baseline or microbiological characteristics, except for a high frequency of previous SBP history in the N-SBP population (P=0.020). During hospitalization, antibiotic switching and in-hospital mortality were significantly higher for patients with N-SBP than CA-SBP (35.6% vs. 8.9%; P=0.001 and 30.4% vs. 12.9%; P=0.028). There were 202 (81.5%) deaths during the follow-up period, with longer overall survival time in patients with CA-SBP (7.9 vs. 3.9 months; P=0.041). However, time to recurrence was not significantly different between the two groups (4.7 vs. 3.6 months; P=0.910). CONCLUSIONS: N-SBP was significantly associated with increased antibiotic switching, higher in-hospital mortality and shorter overall survival. Third-generation cephalosporin may be inappropriate as first-line empirical antibiotics for patients with N-SBP.

Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma.

BACKGROUND: Although sorafenib is accepted as the standard of care in advanced hepatocellular carcinoma (HCC), its therapeutic benefit is marginal. Here, we aimed to compare the efficacy and safety of sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs) in advanced HCC. METHODS: From 2007 to 2012, 290 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) with S-M (n = 226) or S-LRTs (n = 64) were reviewed retrospectively. Survival outcomes and treatment-related toxicities between two groups were analyzed. RESULTS: Variables related to tumor burden and liver function were similar between the groups (all P > 0.05). Within the entire population, the S-LRTs group had both longer median overall survival (OS) (8.5 vs 5.5 months, P = 0.001) and progression-free survival (PFS) (5.3 vs 3.0 months, P = 0.002) than the S-M group. Furthermore, the S-LRTs group had longer Os than the S-M group in a subgroup with neither extrahepatic spread (EHS) nor regional nodal involvement (RNI) (18.0 vs 7.8 months, P = 0.019) and in a subgroup with EHS and/or RNI (8.3 vs 4.8 months, P = 0.028). In addition, the S-LRTs group had longer PFS than the S-M group in the subgroup with neither EHS nor RNI (9.6 vs 3.2 months, P = 0.027). TREATMENT: Related toxicity was similar between two groups. CONCLUSION: Combined use of sorafenib and LRTs may provide better treatment outcomes without significantly increasing treatment-related toxicities, even in patients with EHS and/or RNI. Therefore, addition of active LRTs might be considered, if feasible.

Efficacy and safety of pegylated interferon-α2a in patients with lamivudine-resistant HBeAg-positive chronic hepatitis B.

BACKGROUND: Lamivudine resistance develops in up to 80% of patients with chronic hepatitis B (CHB) after 5 years of treatment. Cross-resistance between nucleoside/nucleotide analogues limits management options in these patients. To investigate the role of pegylated interferon-α2a as rescue therapy in these patients, the efficacy and safety of pegylated interferon-α2a between treatment-naive patients and lamivudine-resistant patients with hepatitis B e antigen (HBeAg)-positive CHB were compared. METHODS: A total of 150 HBeAg-positive CHB patients were stratified according to prior treatment. Lamivudine-resistant patients (n=64) and treatment-naive patients (n=86) received pegylated interferon-α2a once-weekly for 48 weeks and were followed-up for an additional 24 weeks. Primary end points were HBeAg loss and HBV DNA <100,000 copies/ml at end of follow-up. RESULTS: A total of 65 (76%) treatment-naive patients and 49 (77%) lamivudine-resistant patients completed treatment and 24 weeks of follow-up. Rates of HBeAg loss were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 23.4%, respectively; P=0.8423). Similarly, rates of HBV DNA<100,000 copies/ml were comparable at end of follow-up between treatment-naive patients and lamivudine-resistant patients (20.9% and 21.9%, respectively; P=1.000). There was no statistically significant difference in alanine aminotransferase normalization rates between treatment-naive patients and lamivudine-resistant patients (36.0% and 29.7%, respectively; P=0.4848). A total of one patient in each group achieved hepatitis B surface antigen (HBsAg) loss and seroconversion. The most common adverse events were those known to occur with pegylated interferon-α2a therapy, and safety profiles were similar between both patient populations. CONCLUSIONS: Pegylated interferon-α2a may be effective as a rescue therapy in patients with lamivudine-resistant HBeAg-positive CHB.

Association between IL28B polymorphisms and spontaneous clearance of hepatitis B virus infection.

BACKGROUND/AIMS: Single-nucleotide polymorphisms (SNPs) near the interleukin 28B gene (IL28B; interferon [IFN]-λ-3) are associated with outcomes of chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection treated with peginterferon (PEG-IFN) alpha-based antiviral therapy. In this study, we investigated the influence of IL28B polymorphisms on spontaneous clearance of HBV infection in a large Korean cohort. METHODS: Between January 2007 and June 2010, a total of 208 patients with chronic HBV infection and newly diagnosed HBV-related hepatocellular carcinoma were recruited as the CC group [HBsAg(+) for >6 months, anti-HBc(+), and anti-HBs(-)]. In addition, 351 organ donors were stratified into the UE group [n = 106; HBsAg(-), anti-HBc(-), and anti-HBs(-)] or the SC group [n = 245; HBsAg(-), anti-HBc(+), and anti-HBs(+)]. The SNaPshot ddNTP Primer Extension Kit (Applied Biosystems, Foster City, CA) was used for SNP detection. Direct full sequencing of the IL28B coding region was attempted. RESULTS: Regardless of group, rs12979860 CC was most frequently identified (85.0% in UE, 85.9% in SC, and 93.5% in CC, respectively), whereas rs12979860 TT was not identified in any group. Similarly, rs12980275 AA and rs8099917 TT were most frequently identified (≥85%) regardless of group, whereas rs12980275 GG was identified in only one subject in the SC group. In addition, rs8099917 GG was not identified. The prevalences of CC in rs12979860, AA in rs12980275, and TT in rs8099917 were significantly higher in the CC group when compared with the UE and SC group (all P<0.05). Among 19 novel SNPs in the IL28B coding region, the proportions of 6 SNPs were significantly different among the UE, SC, and CC groups (all P<0.05). CONCLUSIONS: The SNP upstream of IL28B that has the strongest genetic association with HCV recovery has an inverse influence on HBV recovery. Additional studies are needed to understand the mechanisms of this SNP in HBV infection.

Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma.

We herein report a patient with advanced hepatitis B virus-related hepatocellular carcinoma (HCC) beyond the Milan criteria. He underwent orthotopic liver transplantation after successful HCC downstaging that satisfied the University of California, San Francisco criteria, using concurrent chemoradiation therapy with a combination of repeated hepatic arterial infusion chemotherapy (HAIC) and sorafenib. A 52-year-old male was diagnosed with advanced hepatitis B virus-related HCC beyond the Milan criteria. He underwent concurrent chemoradiation therapy (50 Gy with 20 fractions over 5 weeks with HAIC using 5-fluorouracil at a dose of 500 mg/day, which was administered during the first and fifth weeks of radiation therapy) as an initial treatment modality. This was followed by the combined use of HAIC using 5-fluorouracil (500 mg/m(2) for 5 hours on days 1-3) and cisplatin (60 mg/m(2) for 2 hours on day 2) every 4 weeks (twelve cycles) and sorafenib (from the third to the twelfth cycle of HAIC) to treat the remaining HCC. Because a remarkable decrease in the tumor burden that satisfied the University of California, San Francisco criteria was observed after these combination treatments, the patient underwent orthotopic liver transplantation with curative aim and survived for 11 months without evidence of HCC recurrence.

Partial virological response to adefovir add-on lamivudine rescue therapy in patients with lamivudine-resistant chronic hepatitis B.

BACKGROUND/AIMS: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. METHODS: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. RESULTS: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. CONCLUSIONS: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.

Quasispecies and pre-existing drug-resistant mutations of hepatitis B virus in patients with chronic hepatitis B.

BACKGROUND/AIMS: To investigate pre-existing hepatitis B virus (HBV) quasispecies and the genotypic evolution of several variants. METHODS: From six patients with lamivudine (LAM) failure, serum samples at pretreatment, 6 months of LAM therapy, and virologic breakthrough were obtained. One hundred clones with HBV inserts in each patient were sequenced at each time point. Pretreatment serum samples were also analyzed from six patients who achieved good responses to LAM therapy. RESULTS: Among the six patients with LAM failure, the analysis of 100 clones from patient 1 revealed the substitutions L180M in 1% of clones and V173L in 2% of clones. Patient 2 had substitutions of L80V, W153Q, and L180M. In patient 3, mutations conferring resistance to adefovir at V84I (5%), I169L (1%), and N236H (7%) and entecavir at S202G (2%) were detected. Patient 4 had mutations at T128N (1%), I169L (1%), V173L (2%), A181V (1%), and Q215H (1%). In patient 5, M204V/I was detected in 1% and 2% of clones, respectively. L80I and V173L were also identified in patient 6. In the six patients who responded to LAM, the degree of overall quasispecies was less than those with LAM failure. CONCLUSIONS: Various HBV quasispecies associated with drug resistance existed before treatment, and the quasispecies dynamically changed through LAM therapy.

Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B.

BACKGROUND/AIMS: The incidence of multidrug-resistant (MDR) chronic hepatitis B (CHB) during sequential lamivudine (LAM) and adefovir dipivoxil (ADV) treatment is increasing. We investigated the antiviral efficacies of various rescue regimens in patients who failed sequential LAM-ADV treatment. METHODS: Forty-eight patients (83.3% of whom were HBeAg-positive) who failed sequential LAM-ADV treatment were treated with one of the following regimens: entecavir (ETV) (1 mg) monotherapy (n=16), LAM+ADV combination therapy (n=20), or ETV (1 mg)+ADV combination therapy (n=12). All patients had confirmed genotypic resistance to both LAM and ADV and were evaluated every 12 weeks. RESULTS: The baseline characteristics and treatment duration did not differ significantly among the study groups. During the treatment period (median duration: 100 weeks), the decline of serum HBV DNA from baseline tended to be greatest in the ETV+ADV group at all-time points (week 48: -2.55 log(10) IU/mL, week 96: -4.27 log(10) IU/mL), but the difference was not statistically significant. The ETV+ADV group also tended to have higher virologic response rates at 96 weeks compared to the ETV monotherapy or LAM+ADV groups (40.0% vs. 20.0% or 20.0%, P=0.656), and less virologic breakthrough was observed compared to the ETV monotherapy or LAM+ADV groups (8.3% vs. 37.5% or 30.0%; P=0.219), but again, the differences were not statistically significant. HBeAg loss occurred in one patient in the ETV+ADV group, in two in the ETV monotherapy group, and in none of the LAM+ADV group. The safety profiles were similar in each arm. CONCLUSIONS: There was a nonsignificant tendency toward better antiviral efficacy with ETV+ADV combination therapy compared to LAM+ADV combination therapy and ETV monotherapy for MDR CHB in Korea, where tenofovir is not yet available.

Normal enhanced liver fibrosis (ELF) values in apparently healthy subjects undergoing a health check-up and in living liver donors in South Korea.

BACKGROUND: The enhanced liver fibrosis (ELF) value is a non-invasive serum marker used for assessing liver fibrosis in chronic liver disease. To use the ELF value for the purpose of screening the general population and selecting subpopulations at high risk, it is important to know the normal range of ELF values as a prerequisite. AIMS: We aimed to define the normal range of ELF values by recruiting apparently healthy subjects and investigating factors influencing ELF values in subjects with minimal fibrotic burden. METHODS: ELF values were determined in a cohort of healthy subjects who underwent a health check-up and in healthy living liver donors who were screened for transplantation. None of subjects suffered from chronic heart disease, diabetes mellitus, metabolic syndrome, hepatitis B, hepatitis C, or human immunodeficiency virus infection, systemic autoimmune disease or liver dysfunction. RESULTS: Among 183 subjects analyzed, the normal ELF 5th through 95th percentile range was 5.95-8.73. Body mass index (P = 0.014) and male gender (P = 0.015) showed significant positive correlations with ELF value, whereas age did not. In multivariate linear regression analysis, platelet count was identified as the only independent factor influencing the ELF value (ß=-0.006, P = 0.016). When considering the difference in ELF values between genders, the normal range of men was defined to be 6.72-8.93, this was slightly higher than that of women, 5.69-8.67. CONCLUSIONS: We identified the normal range of ELF values and found that it can be significantly influenced by platelet count even in the healthy population.

Discordance between liver biopsy and FibroTest in assessing liver fibrosis in chronic hepatitis B.

BACKGROUND AND AIMS: The FibroTest (FT) demonstrated excellent diagnostic performance in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Here, we aimed to identify predictors of discordance between FT and liver biopsy (LB) in Asian patients with CHB. METHODS: Consecutive patients with CHB who underwent both LB and FT on the same day between 2007 and 2010 were recruited from three medical institutes. Laboratory evaluations including specific parameters for calculating FT score, such as α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl transpeptidase, and total bilirubin levels, were obtained. The Batts and Ludwig scoring system was used for histological analysis. RESULTS: A total of 330 patients (200 male and 130 female) were analyzed. Discordances of at least two fibrosis stages between FT and LB were observed in 30 (9.1%) patients; using FT, fibrosis was underestimated in 25 patients and overestimated in 5 patients with reference to LB. Patients with discordance had a higher proportion of F3-4 (P<0.001) and F4 (P = 0.012) compared with those with nondiscordance. The discordance rate was significantly higher in those with F3-4 than those with F1-2 (15.4% vs. 3.0%, P<0.001). Multivariate analysis demonstrated F3-4 at LB as the only independent factor for discordance (P<0.001; odds ratio 5.95). After adjusting fibrosis stages, neither necroinflammatory activity on histology nor serum ALT level influenced FT values independently. CONCLUSION: Advanced fibrosis stage (F3-4) is the sole factor of discordance between FT and LB in Asian patients with CHB.

Early predictor of mortality due to irreversible posthepatectomy liver failure in patients with hepatocellular carcinoma.

BACKGROUND: Although mortality after liver resection has declined, posthepatectomy liver failure (PHLF) remains a major cause of operative mortality. To date there is not consensus on a definition for PHLF. However, there have been many efforts to define PHLF causing operative mortality. In the present study we sought to identify early predictors of death from irreversible PHLF. MATERIALS AND METHODS: We retrospectively analyzed the medical records of 359 patients with hepatocellular carcinoma who underwent liver resection between March 2000 and December 2010. Various biochemical parameters from postoperative days (POD) 1, 3, 5, and 7 were analyzed and compared with the "50-50" criterion. RESULTS: Operative mortality was 4.7 %. Prothrombin time (PT) <65 % and bilirubin ≥ 38 µmol/L on POD 5 showed the only significant difference as compared with "50-50" criterion. The new combination of bilirubin level and the international normalized ratio showed higher sensitivity, area under the curve, as well as similar accuracy (sensitivity 78.6 vs. 28.6 %; p = 0.002; area under the curve 0.8402 vs. 0.6396; p = 0.00176; accuracy 88.6 vs. 93.4 %; p = 0.090). Multivariate analysis revealed the combination of PT <65 % and bilirubin ≥ 38 µmol/L on POD 5 to be the only independent predictive factor of mortality (odds ratio, 82.29; 95 % confidence interval 8.69-779.64; p < 0.001). CONCLUSIONS: In patients with chronic liver disease who will undergo liver resection the combination of PT <65 % and bilirubin ≥ 38 µmol/L on POD 5 may be a more sensitive predictor than the "50-50" criterion of mortality from PHLF. Although it needs to validated by prospective study, this measure may be applied to select patients receiving artificial liver supports or liver transplantation.