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Rei-Chi Hsueh,1 Wan-Jung Wu,1 Chih-Lin Lin,2 Chun-Jen Liu,3 Yi-Wen Huang,4,5 Jui-Ting Hu,6 Chih-Feng Wu,1 Feng-Yu Sung,1 Wen-Jie Liu,1 Ming-Whei Yu1 1Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 2Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan; 3Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; 4Clinical Research Center, Liver Center and Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 5Division of Gastroenterology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 6Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, TaiwanCorrespondence: Ming-Whei Yu, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No. 17, Xuzhou Road Zhongzheng District, Taipei City, 10055, Taiwan, Email yumw@ntu.edu.twBackground: Coexistence of hepatitis B and nonalcoholic fatty liver disease is common; however, little is known about the impact of hepatic steatosis and its major genetic determinants on the natural history of HBV infection. We aimed to study the effects of hepatic steatosis and PNPLA3 variant p.I148M on the risk of hepatocellular carcinoma (HCC) and the lifetime probability of HBsAg seroclearance, which is associated with functional remission and improved long-term outcome of HBV infection.Methods: We conducted a cohort study of 2385 male, HBsAg-positive Taiwanese civil servants recruited in 1989– 1992, and followed up until 2019. Cox regression with competing-risk models was used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs).Results: Of 2385 participants, 628 experienced HBsAg seroclearance and 217 developed HCC. Hepatic steatosis, excess body-mass index, and the PNPLA3-148M variant were significantly associated with higher HBsAg seroclearance rate. However, multivariate analyses accounting for HBsAg seroclearance and various HCC risk factors showed that, while steatosis was associated with decreased HCC risk (sHR [95% CI]: 0.49 [0.36– 0.66]), carriage of the PNPLA3-148M variant allele (vs II homozygotes: 1.64 [1.20– 2.25] for MI heterozygotes; 1.83 [1.20– 2.78] for MM homozygotes) and obesity (1.51 [1.07– 2.13]) were associated with increased risk. The inverse hepatic steatosis-HCC association persisted after additional adjustment for other viral factors or using different follow-up time cut-offs to account for reverse causality. Moreover, the PNPLA3 MM genotype was positively associated with elevations of ALT and AST and liver cirrhosis, while hepatic steatosis was positively associated with ALT but inversely associated with AST and liver cirrhosis.Conclusion: Hepatic steatosis and PNPLA3-148M variant appeared to have distinct impacts on the development of HBV-related progressive liver disease and HCC. PNPLA3 p.I148M, but not a diagnosis of hepatic steatosis, can help to identify HBV carriers with high-risk fatty liver disease in the progression to HCC.Keywords: chronic hepatitis B, HBsAg seroclearance, hepatic steatosis, hepatocellular carcinoma, liver cirrhosis, PNPLA3

Background/aims Direct‐acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)‐infected patients. The real‐world treatment outcome in Taiwanese patients on a nationwide basis is elusive. Methods The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end‐of‐treatment). Results A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype‐1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment‐naïve noncirrhotic, treatment‐naïve cirrhotic, treatment‐experienced noncirrhotic and treatment‐experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment‐experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment‐naïve noncirrhotic patients (94.8%) and treatment‐experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence

Pangenotypic direct-acting antivirals are expected to cure hepatitis C virus (HCV) in more than 95% of treated patients. However, data on the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) in Taiwan are limited. This study aims to characterize the patient population in the nationwide Taiwan Association for the Study of the Liver (TASL) HCV Registry and evaluate treatment outcome in Taiwanese patients receiving SOF/VEL.This study was a retrospective-prospective, observational, multicenter, real-world analysis. Adults with chronic hepatitis C were treated with SOF/VEL 400/100 mg ± ribavirin for 12 weeks. The primary outcome was sustained virologic response 12 weeks after end of therapy (SVR12). Factors associated with not achieving SVR12 were evaluated using logistic regression and covariate analysis. Safety was also assessed.In total, 3480 patients were included: 86.8% genotype 1/2, 2.8% genotype 3, 0.1% genotype 4/5, 9.6% genotype 6; unclassified, 0.8%; 12.2% compensated cirrhosis; 3.3% decompensated cirrhosis; and 15.8% chronic kidney disease. Overall SVR12 rate was 99.4% (genotype 1, 99.5%; genotype 2, 99.4%; genotype 3, 96.9%; genotype 4, 100%; genotype 6, 99.7%). SVR12 rates among patients with compensated cirrhosis, decompensated cirrhosis, and chronic kidney disease stages 4-5 were 99.5%, 100%, and 100%, respectively. There were 21 patients (0.6%) who did not achieve SVR12. Factors associated with failure were treatment adherence below 60%, high viral load, and genotype 3 (p 0.001, p = 0.028, and p = 0.001, respectively). Adverse events occurred in 10% of patients; 0.6% were serious and one was related to treatment. Treatment discontinuation occurred in 0.3% of patients; none were treatment related. The estimated glomerular filtration rate remained stable throughout treatment and follow-up, regardless of baseline values and cirrhosis status.SOF/VEL was highly effective and well tolerated in Taiwanese patients, irrespective of viral genotype, liver disease severity, and comorbidities.

Background/AimsThe study evaluated the real-world treatment outcomes of Glecaprevir/pibrentasvir (GLE/PIB) including effectiveness, safety and healthcare resource utilization based on a nation-wide registry in Taiwan.MethodsThe Taiwan HCV Registry (TACR) is a nation-wide platform organized and supervised by the Taiwan Association for the Study of the Liver. Data were analyzed for patients treated with GLE/PIB, including 3,144 patients who had treatment outcome available. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA throughout 12 weeks of end-of-treatment). ResultsThe overall SVR12 rate was 98.9% (3110/3144), with 98.8%, 99.4% and 100% in patients receiving 8 weeks, 12 weeks, and 16 weeks of GLE/PIB respectively. The SVR12 rate in the treatment-naïve cirrhotic patients receiving 8 weeks of GLE/PIB was 98.2% (108/110). The most common AEs were fatigue (7.5%), pruritus (6.7%) and dizziness (1.5%). The mean number of outpatient visits during the GLE/PIB was 5.94 visits for patients treated with 8 weeks, significantly different from the patients treated with 12 weeks of GLE/PIB (6.90 visits). ConclusionsThe results support the effectiveness and safety of GLE/PIB treatment in real-world clinical practice, and provide further evidence that the shorter, 8-week GLE/PIB regimen is effective and cost-saving.

Controversies over the use of alpha-fetoprotein (AFP) for detection of hepatocellular carcinoma (HCC) existed from guidelines. Using large-scale database and hospital-based information, we aimed to reappraise the role of AFP in HCC surveillance, including proportion of AFP elevation by stage of HCC, additional benefit of AFP in combination of ultrasonography (US) in the detection of early HCC, and survival in early HCC with high AFP levels.This retrospective study enrolled 43,437 patients from database of the Taiwan Cancer Registry (TCR) and 4250 patients from Kaohsiung Chang Gung Memorial Hospital (KCGMH) between January 2011 and December 2017.The HCC cases in KCGMH accounted for 9.8% of the total cases in the TCR. Among both nationwide database and hospital-based information, the proportion of early HCC patients with an AFP level of ≥20 ng/mL was approximately 40%. In KCGMH, the proportion of patients with an AFP level of ≥20 ng/mL and a virus-related (hepatitis B and C) etiology was around 41.7%; furthermore, among patients with early HCC, those with an AFP level of ≥20 ng/mL had 4.7 years of median survival and 48.3% of the 5-year overall survival rate. By hospital electronic medical records review of early HCC cohort in KCGMH, approximately 10.9% of patients with AFP levels ≥20 ng/mL had US-undetectable early HCC.This study suggested that AFP in combination with US would add an additional benefit as being a prompted role for detection of early HCC in patients with US-undetectable HCC.

The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR.Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12).5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common.LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.

The role of heavy alcohol intake, aldehyde dehydrogenase 2 gene (ALDH2) rs671 polymorphism, and hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development and mortality remains uncertain.To investigate the association of heavy alcohol intake, ALDH2 rs671 polymorphism, and HBV infection with HCC development and mortality in patients with cirrhosis.This retrospective cohort study enrolled patients with cirrhosis with heavy alcoholism or/and HBV infection from January 2005 to December 2020. Patients were followed up through June 30, 2021. The current data analysis was performed from August 2021 to April 2022. Patients from 3 tertiary hospitals in Taiwan were enrolled.Heavy alcohol intake was defined as consuming more than 80 g of ethanol each day for at least 5 years.The primary end point was newly developed HCC. The secondary end point was overall mortality.Of 1515 patients with cirrhosis (342 with concomitant heavy alcoholism and HBV infection, 796 with HBV infection alone, and 377 with heavy alcoholism alone), 1277 (84.3%) were men, and their mean (SD) age was 49.5 (10.2) years; 746 patients had blood samples collected for ALDH2 rs671 polymorphism analysis. The 10-year cumulative incidences of HCC and mortality were significantly higher in patients with cirrhosis with concomitant HBV infection and alcoholism than in those with HBV infection alone or alcoholism alone. Heavy alcohol intake and the ALDH2 rs671 genotype (GA/AA) were associated with significantly increased risk of HCC and mortality in patients with HBV-related cirrhosis. In patients with cirrhosis with concomitant HBV infection and alcoholism, factors associated with risk of HCC were baseline serum HBV DNA (adjusted hazard ratio [aHR], 3.24; 95% CI, 1.43-7.31), antiviral therapy (aHR, 0.15; 95% CI, 0.05-0.39), alcohol intake (aHR, 1.78; 95% CI, 1.02-3.12), abstinence (aHR, 0.32; 95% CI, 0.18-0.59), and ALDH2 rs671 polymorphism (aHR, 5.61; 95% CI, 2.42-12.90). Factors associated with increased risk of mortality were abstinence (aHR, 0.25; 95% CI, 0.16-0.32), ALDH2 rs671 polymorphism (aHR, 1.58; 95% CI, 1.09-2.26), Child-Pugh class B vs A (aHR, 1.43; 95% CI, 1.13-2.25) and class C vs A (aHR, 1.98; 95% CI, 1.18-3.31), serum albumin (aHR, 0.61; 95% CI, 0.43-0.86), and HCC development (aHR, 1.68; 95% CI, 1.12-2.89).These findings suggest that heavy alcohol intake and ALDH2 rs671 polymorphism are associated with significantly increased risk of HCC development and mortality in patients with HBV-related cirrhosis. Patients with these risk factors should be monitored closely for HCC.

Simple Summary ALDH2, mitochondrial aldehyde dehydrogenase 2, is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism. The prevalence of the ALDH2*2 variant is 45% in the Taiwanese population. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in modulation of metabolic syndromes remain unclear. The study evaluated the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. We explored the effects of ALDH2 gene on NAFLD and potential association with gut microbiota. Abstract Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism and plays a key role in protecting the liver. The ALDH2*2 mutation causes a significant decrease in acetaldehyde scavenging capacity, leading to the accumulation of acetaldehyde after consuming alcohol. The prevalence of the ALDH2*2 variant is in 45% of Taiwanese individuals. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in the modulation of metabolic syndromes remain unclear. This study evaluates the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. Male (M) and female (F) wild-type (WT) and ALDH2 knock-in C57BL/6J mice (4–5 weeks old) were fed a high-fat diet for 16 weeks. Results showed that the body and white-adipose-tissue weights were significantly increased in ALDH2-M compared to those in the other groups. We observed markedly elevated serum levels of alanine transaminase and glucose. Oral glucose-tolerance test and homeostasis-model assessment of insulin resistance (HOMA-IR) values were significantly higher in ALDH2-M mice than those in WT-M mice, with no observable differences in female mice. Abundant steatosis and inflammatory cells were observed in ALDH2-M, with significantly decreased expression of hepatic genes IRS2, GLUT4, and PGC-1α compared to that in WT-M. ALDH2 gene mutation also affected the β-diversity of gut microbiota in ALDH2-M resulting in the decreased abundance of Actinobacteria and an increase in Deferribacteres. Our results suggest that potential changes in gut microbiota may be associated with the defective ALDH2 exacerbation of high-fat-diet-induced liver diseases in male mice. However, female mice were not affected, and sex hormones may be an important factor that requires further investigation.

Background & Aims Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive. Methods The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non–sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT). Results The eGFR decreased from baseline (91.4 mL/min/1.73 m2) to EOT (88.4 mL/min/1.73 m2; P 90 mL/min/1.73 m2 was the only factor independently associated with significant slope coefficient differences of eGFR (–1.98 mL/min/1.73 m2; 95% confidence interval, –2.24 to –1.72; P Conclusions Both sofosbuvir and non–sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.

Variceal hemorrhage is a major complication of cirrhosis of various etiologies. The clinical management of variceal hemorrhage is pivotal in saving lives. The hemorrhage of varices may recur if portal hypertension persists. Thus, it is important to treat the underlying causes of cirrhosis. In the Asia-Pacific regions, chronic viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease are the most common causes of cirrhosis and varices. The present chapter intends to discuss the clinical features of these disorders.

Lymphoid enhancer factor 1 (LEF1) activity is associated with progression of several types of cancers. The role of LEF1 in progression of hepatocellular carcinoma (HCC) remains poorly known. We investigated LEF1 expression in HCC and its interactions with epithelial‐mesenchymal transition (EMT) regulators (e.g., Snail, Slug, Twist) and stemness genes (e.g., octamer‐binding transcription factor 4 [Oct4], sex determining region Y‐box 2 [Sox2], Nanog homeobox [Nanog]). Microarray analysis was performed on resected tumor samples from patients with HCC with or without postoperative recurrence. LEF1 expression was associated with postoperative recurrence as validated by immunohistochemical staining in another HCC cohort. Among 74 patients, 44 displayed a relatively high percentage of LEF1 staining (>30% of HCC cells), which was associated with a reduced recurrence‐free interval (P < 0.001) and overall survival (P = 0.009). In multivariate analysis, a high percentage of LEF1 staining was significantly associated with low albumin level (P = 0.035), Twist overexpression (P = 0.018), Snail overexpression (P = 0.064), co‐expression of Twist and Snail (P = 0.054), and multinodular tumors (P = 0.025). Down‐regulation of LEF1 by short hairpin RNA decreased tumor sphere formation, soft agar colony formation, and transwell invasiveness of HCC cell lines Mahlavu and PLC. Xenotransplant and tail vein injection experiments revealed that LEF1 down‐regulation in Mahlavu reduced tumor size and metastasis. LEF1 up‐regulation in Huh7 increased sphere formation, soft agar colony formation, and transwell invasiveness. LEF1 was shown to physically interact with and transcriptionally activate promoter regions of Oct4, Snail, Slug, and Twist. Furthermore, Oct4, Snail, and Twist transactivated LEF1 to form a regulatory positive‐feedback loop. Conclusion: LEF1 plays a pivotal role in HCC progression through transcriptional regulation of Oct4 and EMT regulators.

The diagnosis of primary hepatocellular carcinoma (HCC) in high risk patients, such as those with chronic hepatitis B or C with/without cirrhosis of the liver, can be made with relevant image studies alone; however, morphologic confirmation by cytology or histopathology is essential to the diagnosis of metastatic HCC because the treatment of the latter differs from that of primary extrahepatic malignancy. Although both cytology and histopathology are important tools in the diagnosis of malignancy, histopathology almost always plays a confirmatory and pivotal role, and also a gold standard in cyto-histological correlation. We present two patients of metastatic HCC to rare sites; endobronchus in one, and neck lymph nodes, face and the abdominal wall in the other. Repeated bronchial biopsy in the first patient and excisional biopsy from the metastatic sites of the second patient failed to make a conclusive diagnosis of metastatic HCC. However, bronchial brushing in the first patient and fine needle aspiration cytology from the respective metastatic sites of the second patient consistently showed characteristic HCC features and provided clinicians with the rationale for ongoing treatment. The diagnostic issues and possible pitfalls are discussed. Cytology and histopathology appear equipollent; sometimes cytology can play a diagnostic role when histopathology fails its expected role in this scenario.

Chi-Chun Huang,1 Hsin-Yi Chen,1 Ruei-Hsin Chang,1 Pen-An Liao,2 Heng-Hui Lien,3,4 Chih-Sheng Hung,5 Sien-Sing Yang,1,3 Jui-Ting Hu1,3 1Liver Center, Cathay General Hospital Medical Center, Taipei, Taiwan; 2Department of Radiology, Cathay General Hospital Medical Center, Taipei, Taiwan; 3School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan; 4Department of Surgery, Cathay General Hospital Medical Center, Taipei, Taiwan; 5Department of Gastroenterology, Cathay General Hospital Medical Center, Taipei, Taiwan Background: Sorafenib is an oral tyrosine kinase inhibitor that is indicated for advanced hepatocellular carcinoma (HCC). The aim of the present study was to determine the clinical outcomes of HCC patients receiving sorafenib in real-life clinical setting in comparison with formal clinical trials.Methods: Patients diagnosed with advanced HCC between 2007 and 2015 at single institute were retrospectively enrolled and evaluated for survival and tolerability following sorafenib treatment. Overall survival (OS) and duration of treatment (TTP) were examined by different stratifications including age, gender, etiology, liver functions, and severities.Results: A total of 67 advanced HCC patients were enrolled for analysis. Of the 67 eligible patients, 66 patients (99%) were diagnosed as Barcelona Clinic Liver Cancer stage C and 45 (67%) were Child-Pugh A. Chronic hepatitis B virus infection was the main etiology (67%), followed by hepatitis C virus infection (12%) and alcohol liver disease (8%). The median duration of treatment was 3.0 months (95% CI 2.6–3.4 months) and median OS was 8.0 months (95% CI 5.0–11.0 months). By multivariate analysis, female gender (HR =2.462, 95% CI 1.126–5.387, P=0.024), Child-Pugh C (HR =3.913, 95% CI 1.063–14.410, P=0.04), extrahepatic spread (HR =2.123, 95% CI 1.122–4.015, P=0.021), and combined other therapies (HR =0.410, 95% CI 0.117–0.949, P=0.037) were the independent predictors of OS.Conclusion: OS of advanced HCC patients treated with sorafenib was longer than that reported in the Asia-Pacific trial study. Impaired hepatic functions are associated with the shorter survival in real-life setting. Keywords: advanced hepatocellular carcinoma, sorafenib, liver function, tumor burden

This corrects the article DOI: 10.1038/ajg.2017.494.

The effect of diabetes on cirrhosis, its decompensation, and their time relationship in chronic hepatitis C (CHC) patients remains unclear. We conducted a nation-wide cohort study by using the Taiwanese National Health Insurance Research Database, which is comprised of data from >99% of the entire population. Among having randomly sampled 1 million enrollees, 6,251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in CHC patients who were given the diagnosis in the years 1999-2003, but not in 1997-1998. The cohorts of CHC with new-onset diabetes (n = 424) and nondiabetes (n = 1,708) were followed up from inception point in diabetes and from year 1999 in the nondiabetes cohort until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. Kaplan-Meier's survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR] = 1.53; 95% confidence interval [CI] = 1.11-2.11; log-rank test; P

Background: The purpose of this study was to report the safety of perfluorobutane (Sonazoid) as a vascular-phase imaging agent in characterizing focal liver lesions (FLLs). Materials and Methods: From May 2014 to April 2015, a total of 54 individuals who received Sonazoid contrast-enhanced ultrasound (CEUS) were enrolled at 5 hospitals of 4 medical centers. All individuals were included in safety evaluation. A prospective study to evaluate the adverse effect (AE) incidences after intravenous administration of Sonazoid. Results: Sonazoid was well tolerated. Treatment-emergent adverse events (TEAEs) representing AE were recorded for 13 (24.1%) patients. The most common AE was abdominal pain (9.3%), followed by heart rate irregularity (5.6%). The majority of these patients (69.2%) experienced TEAEs that were mild in intensity. Sonazoid causes no significant AEs after intravenous injection. The only noteworthy AEs are related to tolerable myalgia (3.7%), abdominal pain (1.9%), and headache (1.9%). None of the 54 patients showed serious adverse effects. Conclusion: Sonazoid shows good safety and tolerance of intravenous use during CEUS of the liver for evaluation of FLLs.

Background Chronic hepatitis B (CHB) patients display Toll-like receptor 9 (TLR9)-dependent defective immune responses. We aimed to study TLR9 expression on CHB patients and its alteration during therapy. Methods We compared TLR9 expression on fresh peripheral CD14+ monocytes from a cohort of 97 CHB patients and 35 HBsAg-negative, anti-HCV-negative controls, during pegylated interferon or entecavir therapy. TLR9 expression on liver tissue was also investigated. Results Compared with controls, peripheral CD14+ monocytes of CHB patients displayed reduced expression of TLR9 mean fluorescence intensity (MFI; 9.90 ±3.64 versus 7.95 ±3.61; P=0.007) independent of age, gender and alanine aminotransferase (ALT; -2.09, 95% CI -3.568, -0.613; P=0.006). Furthermore, age, gender, ALT, HBeAg status, quantitative HBsAg (qHBsAg) or HBV DNA did not predict the TLR9 expression ( P=0.863). Hepatic TLR9 messenger RNA (mRNA) was significantly reduced in 54 patients compared with 3 controls (0.45 ±0.32 versus 1-fold). Using response-guided therapy by qHBsAg levels and pretreatment TLR9 MFI as a reference, TLR9 MFI restored to a mean of 1.7- to 2.7-fold in pegylated interferon responders and reduced to a mean of 0.6-to 0.7-fold in non-responders starting from treatment week 12. Among 10 entecavir-treated patients, TLR9 MFI gradually restored to a mean of 1.2- to 2.1-fold starting from treatment week 48. Conclusions CHB patients display reduced TLR9 expression on peripheral CD14+ monocytes, which is independent of host and viral markers, and on liver tissue. Responders to pegylated interferon and those under entecavir demonstrate restoration of TLR9 expression. On-treatment TLR9 expression on peripheral monocytes might predict response to pegylated interferon therapy.

Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients.966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and 202 patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC.Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC.Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.

Summary Background The impact of diabetes for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients remains controversial. Aim To investigate the risk of HCC in CHC patients who develop new onset diabetes. Methods We conducted a nation-wide cohort study by using Taiwanese National Health Insurance Research Database, which comprised of data from >99% of entire population. Among randomly sampled one million enrollees, 6251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in the patient who was given the diagnosis in the years 1999–2009 but not in 1997–1998. The cohorts of CHC with new onset diabetes (n = 1100) and 1:1 ratio age-, gender-, and inception point (onset date of diabetes) matched nondiabetes (n = 1087) were followed up from the inception point until the development of HCC, withdrawal from insurance, or December 2009. Results After adjustment for competing mortality, patients with new onset diabetes had a significantly higher cumulative incidence of HCC (Relative Risk = 1.544, 95% CI = 1.000–2.387, modified log-rank test, P = 0.047) as compared to those without. After adjustment for age, gender, cirrhosis, hyperlipidaemia, CHC treatment, diabetes treatment, comorbidity index, obesity and statins therapy by Cox proportional hazard model, diabetes was still an independent predictor for HCC (hazard ratio (HR) = 1.906, 95% CI = 1.102–3.295, P = 0.021). The risk for HCC was increased in those who were 40–59 years old, independent of other variables (HR = 3.086, 95% CI = 1.045–9.112, P = 0.041), and after adjustment for competing mortality (modified log-rank test, P = 0.009). Conclusion Chronic hepatitis C patients who develop diabetes are at an increased risk of hepatocellular carcinoma over time.

Background Serum HBV RNA is detectable during nucleoside/nucleotide analogue therapy as a result of unaffected RNA replicative intermediates or interrupted reverse transcription. We studied the predictive value of serum HBV RNA for initial virological response during nucleoside analogue therapy. Methods Serum HBV RNA was quantified before and at 12 and 24 weeks of lamivudine or entecavir therapy. Serum HBV DNA was measured every 4–12 weeks during treatment to define initial virological response. Results Serum HBV RNA was detectable in 21 of 52 (40%) consecutive patients with a mean of 5.2 log copies/ml (male/female 35/17, mean age of 60 years with a range of 31–82, 44% HBeAg-positive, and 26 with lamivudine and 26 with entecavir) before treatment. Serum HBV RNA level at week 12 in patients with an interval from detectable to undetectable serum HBV DNA level Conclusions Low serum HBV RNA level at week 12 of nucleoside analogue therapy independently predicts initial virological response in treated chronic hepatitis B patients. Serum HBV RNA levels may thus be useful for optimizing treatment of chronic hepatitis B.